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Sample records for patienten mit aml

  1. Kompressionstherapie bei Patienten mit Ulcus cruris venosum.

    PubMed

    Dissemond, Joachim; Assenheimer, Bernd; Bültemann, Anke; Gerber, Veronika; Gretener, Silvia; Kohler-von Siebenthal, Elisabeth; Koller, Sonja; Kröger, Knut; Kurz, Peter; Läuchli, Severin; Münter, Christian; Panfil, Eva-Maria; Probst, Sebastian; Protz, Kerstin; Riepe, Gunnar; Strohal, Robert; Traber, Jürg; Partsch, Hugo

    2016-11-01

    Wund-D.A.CH. ist der Dachverband deutschsprachiger Fachgesellschaften, die sich mit den Thematiken der Wundbehandlung beschäftigen. Experten verschiedener Fachgesellschaften aus Deutschland, Österreich und der Schweiz haben nun einen aktuellen Konsens der Kompressionstherapie für Patienten mit Ulcus cruris venosum erstellt. In Europa ist das Ulcus cruris venosum eine der häufigsten Ursachen für chronische Wunden. Neben der konservativen und interventionellen Wund- und Venentherapie, ist die Kompressionstherapie die Basis der Behandlungsstrategien. Die Kompressionstherapie kann heute mit sehr unterschiedlichen Materialien und Systemen durchgeführt werden. Während in der Entstauungsphase insbesondere Verbände mit Kurzzugbinden oder Mehrkomponentensysteme zur Anwendung kommen, sind es anschließend überwiegend Ulkus-Strumpfsysteme. Eine weitere, bislang wenig verbreitete Alternative sind adaptive Kompressionsbandagen. Insbesondere für die Rezidivprophylaxe werden medizinische Kompressionsstrümpfe empfohlen. Durch die Vielzahl der heute zur Verfügung stehenden Behandlungsoptionen, kann für nahezu alle Patienten ein Konzept entwickelt werden, dass sich an den individuellen Bedürfnissen und Fähigkeiten orientiert und daher auch akzeptiert und durchgeführt wird. Die Kompressionstherapie ist für die Behandlung von Patienten mit Ulcus cruris venosum essentiell. In den letzten Jahren sind viele verschiedene Therapieoptionen verfügbar, die in den deutschsprachigen Ländern unterschiedlich angewendet oder durchgeführt werden. Daher soll dieser Expertenkonsens dazu beitragen, konkrete Empfehlungen für die praktische Durchführung der Kompressionstherapie von Patienten mit Ulcus cruris venosum darzustellen. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  2. Nagelbefall kann bei Patienten mit Psoriasis auf eine Enthesiopathie hinweisen.

    PubMed

    Castellanos-González, Maria; Joven, Beatriz Esther; Sánchez, Julio; Andrés-Esteban, Eva María; Vanaclocha-Sebastián, Francisco; Romero, Pablo Ortiz; Díaz, Raquel Rivera

    2016-11-01

    Obwohl subklinische Enthesiopathie ein gut etabliertes diagnostisches Merkmal der Psoriasisarthritis (PsA) ist, wird sie häufig übersehen, da viele Patienten asymptomatisch sind. Gäbe es klinische Hinweise auf das Vorliegen einer Enthesiopathie, würde dies den Klinikern die Möglichkeit eröffnen, eine PsA frühzeitig zu diagnostizieren. Es wurde eine monozentrische prospektive Studie mit insgesamt 90 Psoriasis-Patienten durchgeführt, um mittels Ultraschall das Vorliegen von Enthesenanomalien zu untersuchen und eine Korrelation mit dem Befall der Nägel festzustellen. Enthesenanomalien wurden bei 23 Patienten (25,5 %) gefunden, von denen 19 (82,6 %) Nagelbefall aufwiesen. Bei 4 Patienten waren die Nägel nicht betroffen. Enthesiopathie lag bei 31,1 % (19/61) der Patienten mit Onychopathie vor, von den Patienten ohne Nagelbefall litten nur 13,8 % (4/29) an Enthesiopathie (p = 0,07). Zwischen dem Target-NAPSI-Score und dem Vorliegen einer Enthesiopathie bestand eine signifikante Korrelation. Eine signifikante Korrelation bestand darüber hinaus auch zwischen dem Vorliegen einer Enthesiopathie und der Anzahl der betroffenen Nägel (p = 0,035). Klinische Belege für eine Onychopathie können der Schlüssel für die frühe Diagnose einer Enthesiopathie bei Psoriasis-Patienten sein. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  3. Kompressionstherapie - Versorgungspraxis: Informationsstand von Patienten mit Ulcus cruris venosum.

    PubMed

    Protz, Kerstin; Heyer, Kristina; Dissemond, Joachim; Temme, Barbara; Münter, Karl-Christian; Verheyen-Cronau, Ida; Klose, Katharina; Hampel-Kalthoff, Carsten; Augustin, Matthias

    2016-12-01

    Eine Säule der kausalen Therapie bei Patienten mit Ulcus cruris venosum ist die Kompressionstherapie. Sie unterstützt die Abheilung, reduziert Schmerzen und Rezidive und steigert die Lebensqualität. Bislang existieren kaum wissenschaftliche Daten zu dem Versorgungsstand und fachspezifischem Wissen von Patienten mit Ulcus cruris venosum. Standardisierte Fragebögen wurden bundesweit in 55 Pflegediensten, 32 Arztpraxen, vier Wundzentren und -sprechstunden sowie einem Pflegetherapiestützpunkt von Patienten mit Ulcus cruris venosum bei Erstvorstellung anonym ausgefüllt. Insgesamt nahmen 177 Patienten (Durchschnittsalter 69,4 Jahre; 75,1 % Frauen) teil. Ein florides Ulcus cruris venosum bestand im Mittel 17 Monate. 31,1 % hatten keine Kompressionstherapie, 40,1 % Binden und 28,8 % Strümpfe. Bei der Bestrumpfung hatten 13,7 % Kompressionsklasse III, 64,7 % Kompressionsklasse II und 19,6 % Kompressionsklasse I. 70,6 % legten die Strümpfe nach dem Aufstehen an, 21,1 % trugen sie Tag und Nacht. 39,2 % bereiteten die Strümpfe Beschwerden. Lediglich 11,7 % hatten eine An- und Ausziehhilfe. Die Binden wurden im Mittel 40,7 Wochen getragen und bei 69 % nicht unterpolstert. Bei 2,8 % wurde der Knöchel- und Waden-Umfang zur Erfolgskontrolle gemessen. Venensport machten 45,9 %. Ein Drittel hatte keine Kompressionsversorgung, obwohl diese eine Basismaßnahme der Therapie des Ulcus cruris venosum ist. Zudem ist deren korrekte Auswahl und Anwendung angesichts der langen Bestandsdauer der Ulzerationen zu hinterfragen. Weiterführende Fachkenntnisse bei Anwendern und Verordnern sowie Patientenschulungen sind erforderlich. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  4. [COPD und Klangtherapie: Pilotstudie zur Wirksamkeit einer Behandlung mit Körpertambura bei COPD-Patienten].

    PubMed

    Hartwig, Bernhard; Schmidt, Stefan; Hartwig, Isabella

    2016-01-01

    Hintergrund: Erkrankungen der Atemorgane treten mit steigendem Alter öfter auf, nehmen weltweit zu und sind häufige Ursachen für Morbidität und Mortalität. In dieser Pilotstudie wurde der Frage nachgegangen, ob eine einmalige 10-minütige Behandlung mit einer Körpertambura eine signifikante und effektive Verbesserung der Lungenfunktion von Patienten mit chronisch-obstruktiver Lungenerkrankung (COPD; GOLD-Stadium A oder B) erbringen kann. Patienten und Methoden: 54 Probanden konnten je zur Hälfte in eine Behandlungsgruppe (Körpertambura) und eine aktive Kontrollgruppe (Atemtherapie) randomisiert werden. Eine Bestimmung der Lungenfunktionsmessparameter «Einsekundenkapazität» (FEV1) und «inspiratorische Vitalkapazität» (IVC) zu den Zeitpunkten T1 (Baseline), T2 (direkt nach Behandlung) und als Follow-up etwa 3 Wochen nach T1 (T3). Ergebnisse: Die Behandlungsgruppe zeigte sich der Kontrollgruppe in beiden Werten signifikant überlegen. Die Zeit-×-Gruppe-Interaktion (Varianzanalyse) ergab p = 0,001 (FEV1) bzw. p = 0,04 (IVC). Die Behandlungsgruppe zeigte bei beiden Werten eine Verbesserung von klinischer Relevanz. Schlussfolgerung: Diese Ergebnisse zeigen, dass die Klangbehandlung mittels einer Körpertambura - neben den schulmedizinischen, leitliniengerechten Therapien - eine zusätzliche, nebenwirkungsarme, aber durchaus klinisch wirksame Option für die Behandlung von COPD-Patienten darstellen kann, um deren Lebensqualität zu stabilisieren und zu verbessern. © 2016 S. Karger GmbH, Freiburg.

  5. Gebrauch von Komplementärmedizin bei Patienten mit metastasierendem Melanom unter Therapie mit Ipilimumab innerhalb einer klinischen Studie.

    PubMed

    Huebner, Jutta; Mohr, Peter; Simon, Jan-Christoph; Fluck, Michael; Berking, Carola; Zimmer, Lisa; Loquai, Carmen

    2016-05-01

    In Deutschland wenden 40-90 % aller Krebspatienten Methoden der komplementären and alternativen Medizin (KAM) an. Bis dato gibt es kein Datenmaterial zum Einsatz der KAM bei Melanompatienten. Das Ziel unserer Studie war es, Daten über den Gebrauch, die Informationsquellen und Ziele von Patienten mit metastasierendem Melanom zu erfassen. Einhundertsechsundfünfzig Patienten aus 25 Studienzentren nahmen an der DecOG-MM-PAL Multibasket Studie teil. Die beteiligten Personen wurden auch gebeten, an einer Nebenstudie teilzunehmen, die ihren Gebrauch von KAM erfassen sollte. Dazu wurde während der Behandlung ein standardisierter Fragebogen zu genau festgelegten Zeitpunkten ausgeteilt. Insgesamt gingen 55 Fragebögen von 32 (21 %) Melanompatienten ein. Von diesen gaben 17 (53 %) ein Interesse an KAM an, und sieben (22 %) machten von KAM Gebrauch. Die Hauptinformationsquellen (31 %) waren Familienmitglieder und Freunde, gefolgt von Ärzten (19 %). Die Hauptgründe für die Anwendung von KAM waren die Stärkung des Immunsystems (41 %) und des Körpers (34 %). Nahrungsergänzungsmittel (Vitamine und Spurenelemente) wurden am häufigsten angewendet (28 %). Eine relativ hohe Anzahl an Patienten mit metastasierendem Melanom machte trotz Teilnahme an einer klinischen Studie von KAM Gebrauch. Wechselwirkungen könnten durch biologisch basierte KAM auftreten, und hier besonders bei immunmodulierenden KAM- Strategien. Um Risiken zu vermeiden, sollte die Kommunikation zwischen den Ärzten und den Patienten verbessert werden. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  6. Ustekinumab in der Therapie der Pustulosis palmoplantaris - Eine Fallserie mit neun Patienten.

    PubMed

    Buder, Valeska; Herberger, Katharina; Jacobi, Arnd; Augustin, Matthias; Radtke, Marc Alexander

    2016-11-01

    Die Pustulosis palmoplantaris ist eine chronisch entzündliche Hauterkrankung, die mit bedeutenden Einschränkungen der Lebensqualität und der Belastbarkeit einhergeht. Aufgrund von Zulassungsbeschränkungen und einem häufig therapierefraktären Verlauf sind die Behandlungsmöglichkeiten limitiert. Nach zuvor frustranen Therapien erhielten 9 Patienten mit Pustulosis palmoplantaris nach Ausschluss einer latenten Tuberkulose Ustekinumab (45 mg Ustekinumab bei < 100 kg Körpergewicht [KG], 90 mg Ustekinumab > 100 kg KG) in Woche 0, 4, 12 und 24. Reguläre Visiten erfolgten nach 4 und 12 Wochen, im weiteren Verlauf alle 12 Wochen. Das Durchschnittsalter bei Therapiebeginn betrug 48 Jahre. Drei Patienten waren männlich. Bei n  =  4 Patienten (44,4 %) wurde eine Verbesserung um 75 % des Palmoplantar-Psoriasis-Area-Severity-Index (PPPASI) erreicht. Insgesamt verbesserte sich der PPPASI nach 24 Wochen durchschnittlich um 71,6 %. Eine komplette Abheilung zeigte sich bei n  =  2 Patienten nach 24 Wochen. Bis auf lokale Injektionsreaktionen und leichte Infekte wurden keine unerwünschten Wirkungen beobachtet. Die Fallserie ist ein weiterer Beleg für die Wirksamkeit und Verträglichkeit von Ustekinumab in der Therapie der Pustulosis palmoplantaris. Zur Beurteilung der Langzeitwirkung und -sicherheit sowie der Wirksamkeit einer intermittierenden Therapie sind kontrollierte Studiendaten sowie Beobachtungen im Rahmen von Patientenregistern notwendig. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  7. [Cardiodoron® bei Patienten mit Schlafstörungen - Ergebnisse einer prospektiven Beobachtungsstudie].

    PubMed

    Rother, Claudia; Schnelle, Martin

    2017-01-01

    Hintergrund: Schlafstörungen gehören zu den häufigsten gesundheitlichen Problemen der heutigen Zeit. Stress und die dadurch bedingte innere Anspannung sowie eine unrhythmische Lebensführung z.B. durch Schichtarbeit sind bekannte auslösende Faktoren. Weniger bekannt ist, dass auch funktionelle Herz-Kreislauf-Beschwerden zu Störungen des Schlafs führen können und dass deren Behandlung zu einer Verbesserung der Schlafqualität beiträgt. Ganzheitlich betrachtet geht es daher um die Wiederherstellung einer gesunden Rhythmik, insbesondere des Herz-/Atem- sowie des Schlaf-Wach-Rhythmus, die Cardiodoron®, eine Heilpflanzenkomposition aus Primula veris, Hyoscyamus niger und Onopordum acanthium, unterstützt. Patienten und Methoden: Mittels einer prospektiven, multizentrischen Beobachtungsstudie sollte ermittelt werden, wie sich funktionelle Herz-Kreislauf-Beschwerden und/oder Schlafstörungen unter der Behandlung mit Cardiodoron® (Dilution) über 3-6 Monate entwickeln. Im Zeitraum von September 2009 bis März 2012 dokumentierten 92 Ärzte 501 Patienten, von denen 380 über Schlafstörungen klagten und deren Daten in dieser Publikation näher betrachtet werden. Nach einer Aufnahmeuntersuchung erfolgte nach 90 Tagen eine Abschlussuntersuchung und bei Fortführung der Therapie nach nochmals 90 Tagen eine Follow-up-Untersuchung. Neben 30 ärztlicherseits bewerteten Symptomen beurteilten die Patienten ihr Befinden mittels Pittsburgh Sleep Quality Index (PSQI) nach Buysse und der Beschwerden-Liste nach von Zerssen (B-L und B-L'). Ergebnisse: Unter der Cardiodoron®-Therapie gingen bei guter Verträglichkeit sowohl die Ausprägung der Schlafstörungen (um 65% von 2,0 auf 0,7 Punkte) als auch die erfassten 30 Symptome (um 59% von 24,3 auf 9,9 Punkte) deutlich zurück (p < 0,01). Weiterhin reduzierten sich der PSQI und der Gesamtwert der Beschwerden-Liste signifikant (p < 0,0001) um 60% bzw. 56% (von 12,2 auf 4,8 bzw. von 25,6 auf 11,4 Punkte). Schlussfolgerungen: Bei

  8. Wirksamkeit und Sicherheit von Fumarsäureestern in Kombination mit Phototherapie bei Patienten mit moderater bis schwerer Plaque-Psoriasis (FAST).

    PubMed

    Weisenseel, Peter; Reich, Kristian; Griemberg, Wiebke; Merten, Katharina; Gröschel, Christine; Gomez, Natalie Nunez; Taipale, Kirsi; Bräu, Beate; Zschocke, Ina

    2017-02-01

    Die Behandlung von Psoriasis-Patienten mit einer Kombination aus Fumarsäureestern (FSE, Fumaderm(®) ) und Phototherapie (UV) ist verbreitet, wurde aber im Rahmen von Studien wenig untersucht. Bisher liegen lediglich Daten aus einer kleinen Pilotstudie vor. Intention dieser Studie war, eine FSE/UV-Kombinationsbehandlung an einem größeren Patientenkollektiv mit mittelschwerer bis schwerer Psoriasis zu untersuchen. In dieser prospektiven, multizentrischen, nichtinterventionellen Studie wurden Daten von Patienten mit FSE/UV-Kombinationstherapie hinsichtlich der Wirksamkeit (PGA' PASI, DLQI, EQ-5D), Sicherheit und Dosierung über einen Zeitraum von zwölf Monaten erfasst und mit Daten einer retrospektiven Studie mit FSE-Monotherapie verglichen. Es wurden Daten von 363 Patienten ausgewertet. Unter der Kombinationstherapie verbesserten sich alle Wirksamkeitsparameter deutlich. Im Vergleich zur Monotherapie mit FSE konnte durch die Kombination mit UV ein schnellerer Wirkeintritt erzielt werden, wobei nach zwölf Monaten kein Unterschied in der Wirksamkeit bestand. Die Dauer und Art der Phototherapie zeigte keinen Einfluss auf die Wirksamkeitsparameter. Allgemein wurde die Kombinationstherapie gut vertragen. Unerwünschte Ereignisse wurden bei 7 % der Patienten berichtet. Die FSE/UV Kombinationstherapie zeigt eine gute Wirksamkeit und Verträglichkeit und kann zu einem schnelleren Wirkeintritt führen. Eine Kombinationstherapie erscheint vor allem in den ersten drei Monaten der FSE Behandlung sinnvoll. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  9. Zeitlicher Verlauf der avaskulären Nekrose des Hüftkopfes bei Patienten mit Pemphigus vulgaris.

    PubMed

    Balighi, Kamran; Daneshpazhooh, Maryam; Aghazadeh, Nessa; Saeidi, Vahide; Shahpouri, Farzam; Hejazi, Pardis; Chams-Davatchi, Cheyda

    2016-10-01

    Pemphigus vulgaris (PV) wird in der Regel mit systemischen Corticosteroiden und Immunsuppressiva behandelt. Avaskuläre Nekrose (AVN) des Hüftkopfes ist eine gut bekannte schwerere Komplikation einer Corticosteroid-Therapie. Die Charakteristika dieser schweren Komplikation bei PV sind nach wie vor unbekannt. Nicht kontrollierte, retrospektive Untersuchung aller PV-bedingten AVN-Fälle, die in einer iranischen Klinik für bullöse Autoimmunerkrankungen zwischen 1985 und 2013 diagnostiziert wurden. Anhand der Krankenakten von 2321 untersuchten PV-Patienten wurden 45 Fälle (1,93 %) von femoraler AVN identifiziert. Dreißig davon waren Männer. Das mittlere Alter bei der Diagnose der AVN betrug 47,4 ± 14,2 Jahre. Der mittlere Zeitraum zwischen der Diagnose des PV und dem Einsetzen der AVN lag bei 25,3 ± 18,3 Monaten. Mit Ausnahme von acht Fällen (17,8 %) setzte die AVN bei der Mehrheit der Patienten innerhalb von drei Jahren nach Diagnose des PV ein. Die mittlere kumulative Dosis von Prednisolon bei Patienten mit AVN betrug 13.115,8 ± 7041,1 mg. Zwischen der Prednisolon-Gesamtdosis und dem Zeitraum bis zum Einsetzen der AVN bestand eine starke Korrelation (p = 0,001). Bei Patienten mit Alendronateinnahme in der Vorgeschichte war dieser Zeitraum signifikant kürzer (p = 0,01). Die AVN ist eine schwere Komplikation einer Corticosteroid-Behandlung bei Patienten mit PV. Sie wird bei 2 % der Patienten beobachtet und tritt vor allem in den ersten drei Behandlungsjahren auf. Bei Patienten, die höhere Dosen von Prednisolon erhalten, setzt die AVN tendenziell früher ein. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  10. Retrospektive Analyse von Zufallsbefunden, die bei Patienten mit kutanem malignen Malignom durch (18) F-Fluordeoxyglucose-PET/CT erhoben wurden.

    PubMed

    Conrad, Franziska; Winkens, Thomas; Kaatz, Martin; Goetze, Steven; Freesmeyer, Martin

    2016-08-01

    Bei der (18) F-Fluordeoxyglucose-Positronenemissionstomographie/Computertomographie (FDG-PET/CT) ergeben sich häufig Zufallsbefunde. In der vorliegenden Studie konzentrierten wir uns auf mittels FDG-PET/CT erhaltene Zufallsbefunde bei Patienten mit kutanem Melanom und überprüften deren Relevanz hinsichtlich weiterer diagnostischer Maßnahmen und Interventionen. Die Krankenakten von 181 konsekutiven Melanom-Patienten wurden retrospektiv ausgewertet, um das Management von Zufallsbefunden zu dokumentieren. Der Schwerpunkt lag dabei auf den histologischen Befunden. Bei 33 von 181 (18 %) Patienten lagen 39 relevante Zufallsbefunde vor, und zwar im Kolorektalbereich (n = 15 Patienten), in der Schilddrüse (n = 8), der Prostata (n = 2), dem Bewegungsapparat (n = 2), in Lymphknoten (n = 2), der Parotis (n = 1), den Mandeln (n = 1), den Nieren (n = 1) und der Gallenblase (n = 1). Bei 25 Patienten schlossen sich weitere diagnostische Verfahren an, wobei in 21 Fällen ein klinisches Korrelat nachgewiesen wurde. Bei 16 von 21 Patienten ergab sich eine Neoplasie, darunter fünf maligne Läsionen (vier Kolonkarzinome und ein Prostatakarzinom). Die Malignome wurden frühzeitig diagnostiziert und in der Mehrzahl der Fälle erfolgreich entfernt. Der Einsatz der FDG-PET/CT als Routine-Diagnostik wird in den Leitlinien empfohlen und ist indiziert bei malignem Melanom ab Stadium IIC. In dieser Studie wurden auf effektive Weise ansonsten nicht erkannte Krebserkrankungen, insbesondere Kolonkarzinome, detektiert. In den meisten Fällen war eine frühe Intervention möglich. Zufallsbefunde durch FDG-PET/CT sollten, unter Berücksichtigung des Zustands und der Wünsche des Patienten, mit den geeigneten diagnostischen Maßnahmen abgeklärt werden. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  11. Der Einfluss von Alitretinoin auf die Lebensqualität bei Patienten mit schwerem chronischen Handekzem: FUGETTA - Beobachtungsstudie unter Praxisbedingungen.

    PubMed

    Augustin, Matthias; Thaçi, Diamant; Kamps, Anja

    2016-12-01

    Alitretinoin ist die einzige zugelassene Behandlung für schweres chronisches Handekzem (CHE), das refraktär gegenüber potenten topischen Corticosteroiden ist. Bei dieser Studie (FUGETTA) wurde die Wirksamkeit von leitliniengerecht angewendetem oralem Alitretinoin sowie dessen Einfluss auf die Lebensqualität (LQ) bei Patienten mit schwerem refraktärem CHE beurteilt. Multizentrische, offene, nichtinterventionelle Beobachtungsstudie, durchgeführt in Deutschland. Die Patienten wurden nach Ermessen ihres behandelnden Arztes mit Alitretinoin 10 mg oder 30 mg einmal täglich über maximal 24 Wochen behandelt. Die Wirksamkeit wurde anhand des Physician Global Assessment (PGA) und des Dermatology Life Quality Index (DLQI) bewertet. Zudem wurden unerwünschte Ereignisse (UE) erfasst. Die Studienpopulation bestand aus 658 Patienten (30 mg: n = 581; 10 mg: n = 77). Bei Beobachtungsbeginn litten die meisten Patienten (83 %) gemäß PGA an einem schweren CHE. Bei Beobachtungsende war das Handekzem bei 48 % der Patienten gemäß PGA vollständig oder fast vollständig abgeheilt (30 mg: 49 %; 10 mg: 43 %). Die mittlere Verbesserung des DLQI-Scores in Woche 24 betrug 58 % (30 mg: mittlere [SD] Veränderung gegenüber dem Ausgangswert -10,4 [8,04]) und 70 % (10 mg: mittlere [SD] Veränderung gegenüber dem Ausgangswert -10,8 [7,29]). Die Gesamtinzidenz von NW war niedrig und in den beiden Gruppen ähnlich. Alitretinoin führte zu einer schnellen, deutlichen Verbesserung der LQ bei Patienten mit schwerem CHE. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  12. Krankheitsverlauf, medizinische Versorgung und Lebensqualität von Patienten mit kongenitalen melanozytären Nävi - Auswertung des deutschsprachigen KMN-Registers.

    PubMed

    Elisabeth Wramp, Maria; Langenbruch, Anna; Augustin, Matthias; Zillikens, Detlef; Krengel, Sven

    2017-02-01

    Kongenitale melanozytäre Nävi (KMN) bedeuten für Patienten und Familien eine psychologische Belastung und bergen zudem medizinische Risiken. Das 2005 gegründete deutschsprachige KMN-Register wurde nun einer Zwischenauswertung bezüglich des Krankheitsverlaufes, der medizinischen Versorgung und der Lebensqualität unterzogen. 100 Patienten, die sich in den Jahren 2005 bis 2012 mit einem Erstmeldebogen registriert hatten, wurde im Rahmen einer prospektiven Kohortenstudie Anfang 2013 ein Folgemeldebogen zugesandt. Außerdem wurden mithilfe standardisierter Fragebögen Daten zu Lebensqualität (dermatology life quality index, DLQI) und Stigmatisierungserfahrungen (perceived stigmatization questionnaire, PSQ; social comfort questionnaire, SCQ) erhoben. 83 % der Patienten oder deren Eltern antworteten (Altersdurchschnitt 11,2 Jahre, Median 6 Jahre; mittleres Follow-up 4,4 Jahre). Im Gesamtkollektiv wurden vier Melanome diagnostiziert, davon zwei zerebrale Melanome im Kindesalter, ein kutanes Melanom im Erwachsenenalter und eines, das sich als proliferierender Knoten erwies. Bei vier Kindern wurde eine neurokutane Melanozytose festgestellt, drei davon mit neurologischer Symptomatik. Chirurgisch behandelt wurden 88 % (73/83). Achtundsiebzig Prozent der Befragten berichteten eine geringe oder keine Beeinträchtigung der Lebensqualität. Die wahrgenommene Stigmatisierung beziehungsweise Beeinträchtigung des sozialen Wohlbefindens war generell ebenfalls gering. Die Ergebnisse geben einen Überblick über die Situation von Patienten mit KMN in Deutschland, Österreich und der Schweiz. Ein Melanom entwickelte sich in 3 %, eine ZNS-Beteiligung bestand in 4 % der Fälle. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  13. Acute Myelogenous Leukemia (AML)

    MedlinePlus

    ... chemical exposure. Exposure to certain chemicals, such as benzene, is linked to greater risk of AML. Smoking. AML is linked to cigarette smoke, which contains benzene and other known cancer-causing chemicals. Other blood ...

  14. Intraläsionale Therapie niedrig maligner primär kutaner B-Zell-Lymphome mit Anti-CD20-Antikörper: Nebenwirkungen korrelieren mit gutem klinischen Ansprechen.

    PubMed

    Eberle, Franziska C; Holstein, Julia; Scheu, Alexander; Fend, Falko; Yazdi, Amir S

    2017-03-01

    Die intraläsionale Gabe von Anti-CD20-Antikörpern (Rituximab) wurde als effektive Therapieoption für Patienten mit niedrig malignen primär kutanen B-Zell-Lymphomen beschrieben. Bis heute wurden allerdings keine Parameter identifiziert, welche reproduzierbar ein gutes klinisches Ansprechen dieser Therapie vorhersagen. Ziel dieser Studie ist, sowohl das klinische Ansprechen und die unerwünschten Nebenwirkungen als auch die Patientenwahrnehmung hinsichtlich intraläsionaler Injektionen von anti-CD20-Antikörpern zur Behandlung indolenter primär kutaner B-Zell-Lymphome im Vergleich mit anderen Therapien zu evaluieren. Elf Patienten mit einem primär kutanen B-Zell-Lymphom, namentlich primär kutanes Keimzentrumslymphom (n = 9) und primär kutanes Marginalzonenlymphom (n = 2), welche mittels intraläsionalem Anti-CD20-Antikörper behandelt wurden, wurden retrospektiv evaluiert hinsichtlich der Ansprechrate und unerwünschter Nebenwirkungen sowie in Bezug auf deren Selbsteinschätzung dieser und anderer Therapien des primär kutanen B-Zell-Lymphoms. Patienten, deren primär kutanes B-Zell-Lymphom mittels intraläsionaler Gabe von Anti-CD20-Antikörper behandelt wurde, zeigten ein komplettes oder partielles Ansprechen in 45 % beziehungsweise 27 % aller Patienten. Speziell Patienten mit grippeähnlichen Symptomen nach erfolgter Injektion zeigten ein gutes Ansprechen. Die Mehrheit der Patienten empfand die Therapie mit Rituximab als die beste Therapie im Vergleich zu anderen Therapien wie beispielsweise chirurgische Exzision oder Radiotherapie. Intraläsionales Rituximab ist eine effektive Therapie mit hoher Patientenzufriedenheit. Starke therapiebedingte Nebenwirkungen wie Fieber, Schüttelfrost und Kopfschmerzen nach Gabe von Rituximab könnten als Indikator für gute Wirksamkeit dienen. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  15. Federal Logistics Information System (FLIS). Volume 18. Automated Mailing Labels System (AMLS) FLIS Procedures Manual

    DTIC Science & Technology

    1993-07-01

    LPLPW3t TIME XXXX\\ LISI ADDRESSES AND DISIRIBUTION FOR XX XXXXXXXXXXXXXXXXXX\\ LSER ID XXX P %G[ ZZ.zz9 AA MLG MAILING ADDRESS ZIP CODE PI C x XNXX XX...4100.39-M Volume Is APPENDIX C AMLS INFORMATIONAL MESSAGES Corrective Action: Press the F6 ( COM MIT) function key to add the Distribution information

  16. Emerging therapeutic drugs for AML

    PubMed Central

    Tallman, Martin S.

    2016-01-01

    Multiple new drugs are being developed to treat acute myeloid leukemia (AML), including novel formulations of traditional chemotherapy-antibody drug conjugates and agents that target specific mutant enzymes. Next-generation sequencing has allowed us to discover the genetic mutations that lead to the development and clinical progression of AML. Studies of clonal hierarchy suggest which mutations occur early and dominate. This has led to targeted therapy against mutant driver proteins as well as the development of drugs such as CPX-351 and SGN-CD33A whose mechanisms of action and efficacy may not be dependent on mutational complexity. In this brief review, we discuss drugs that may emerge as important for the treatment of AML in the next 10 years. PMID:26660428

  17. Acute Myeloid Leukemia (AML) (For Parents)

    MedlinePlus

    ... TV, Video Games, and the Internet Acute Myeloid Leukemia (AML) KidsHealth > For Parents > Acute Myeloid Leukemia (AML) ... Treatment Coping en español Leucemia mieloide aguda About Leukemia Leukemia is a type of cancer that affects ...

  18. An Alternative Sugar Fuels AML.

    PubMed

    Cairns, Rob A; Mak, Tak W

    2016-11-14

    Although altered glucose metabolism is a well-studied feature of malignant cells, little is known about the direct metabolism of fructose. In this issue of Cancer Cell, Chen et al. report that AML cells consume fructose and use it to maintain viability, especially when glucose is scarce.

  19. MIT: Shaping the Future.

    ERIC Educational Resources Information Center

    Manning, Kenneth R., Ed.

    This book provides 16 essays by faculty and staff of the Massachusetts Institute of Technology (MIT) concerning what MIT is like today and offering a guide to its possible future. Emphasis is placed on local, national, and global issues, providing a current sampling of the state of concerns and opinions around MIT. Topics include the question of…

  20. MIT: Shaping the Future.

    ERIC Educational Resources Information Center

    Manning, Kenneth R., Ed.

    This book provides 16 essays by faculty and staff of the Massachusetts Institute of Technology (MIT) concerning what MIT is like today and offering a guide to its possible future. Emphasis is placed on local, national, and global issues, providing a current sampling of the state of concerns and opinions around MIT. Topics include the question of…

  1. Neutronenforschung Holographie mit Neutronen

    NASA Astrophysics Data System (ADS)

    Krexner, Gerhard

    2003-01-01

    Jeder kennt sie, die räumlich wirkenden Hologramme, die es seit dreißig Jahren etwa zu kaufen gibt. Sie werden mit sichtbarem Laserlicht erstellt. Grundsätzlich spricht nichts dagegen, Hologramme auch mit Materiewellen anzufertigen. Einer internationalen Forschergruppe gelang kürzlich am Institut Laue-Langevin (ILL) in Grenoble erstmals die holographische Abbildung eines Atomgitters mit Neutronen [1].

  2. Prognostic stratification in the treatment of AML.

    PubMed

    Asou, Norio

    Current treatment of acute myeloid leukemia (AML) still relies on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). AML is a heterogeneous neoplasm characterized by distinct chromosomal and genetic abnormalities. Recent comprehensive gene analyses have highlighted distinct genetic subgroups that are associated with different responses to chemotherapy. Therefore, the molecular landscape of AML is fundamental to the development of novel therapeutic approaches and provides opportunities for individualization of therapy. In addition, the age-related incidence of clonal hematopoiesis is high, affecting nearly 10% of healthy people more than 65 years of age. Clonal hematopoiesis is confirmed by the presence of mutations related to AML including genes involved in DNA methylation, chromatin modification and RNA splicing. In the analysis of gene mutation profiles in secondary AML (s-AML) from myelodysplastic syndromes and myeloproliferative neoplasms, secondary-type gene mutations were identified with >95% specificity in s-AML as compared with de novo AML, including RNA splicing, chromatin modification and cohesion complex genes, and were highly associated with poor responses to chemotherapy as well as TP53 mutation. It is important to identify genetic subgroups at relatively high-risk of relapses who should receive allogeneic HSCT during the first remission. In this review, prognostic stratification for individualized treatment of AML is discussed.

  3. Einsatz und Wirksamkeit von Systemtherapien bei Erwachsenen mit schwerer Neurodermitis: Erste Ergebnisse des deutschen Neurodermitis-Registers TREATgermany.

    PubMed

    Schmitt, Jochen; Abraham, Susanne; Trautmann, Freya; Stephan, Victoria; Fölster-Holst, Regina; Homey, Bernhard; Bieber, Thomas; Novak, Natalija; Sticherling, Michael; Augustin, Matthias; Kleinheinz, Andreas; Elsner, Peter; Weidinger, Stephan; Werfel, Thomas

    2017-01-01

    Versorgungsregister dienen der Erfassung des Einsatzes und der Wirksamkeit von Therapien unter realen Versorgungsbedingungen und sind als Basis einer evidenzbasierten Gesundheitsversorgung unverzichtbar. Das deutsche Neurodermitis-Register TREATgermany wurde als weltweit erstes Register für Patienten mit schwerer Neurodermitis 2011 initiiert. Erwachsene mit schwerer Neurodermitis (aktuelle/frühere antientzündliche Systemtherapie und/oder objektiver SCORAD ≥ 40) werden über einen Zeitraum von 24 Monaten prospektiv beobachtet. Anhand validierter Erhebungsinstrumente werden die klinische Erkrankungsschwere (EASI, SCORAD), Lebensqualität (DLQI), Symptome, globale Erkrankungsschwere sowie die Patientenzufriedenheit erfasst und die durchgeführten Therapien dokumentiert. Die vorliegende Analyse beschreibt die Charakteristika, Therapiewahl und Wirksamkeit der eingesetzten antiinflammatorischen Systemtherapien der bis Oktober 2014 eingeschlossenen Patienten. An fünf Zentren wurden insgesamt 78 Patienten (Durchschnittsalter 39 Jahre, 61 % männlich) eingeschlossen. Bei den Patienten besteht eine hohe Inanspruchnahme ambulanter und stationärer Leistungen. Ciclosporin war das am häufigsten eingesetzte Systemtherapeutikum und zeigte die höchste klinische Effektivität (EASI-50-Ansprechrate 51 %; EASI-75-Ansprechrate 34 % nach zwölfwöchiger Therapie). Azathioprin, Methotrexat (MTX), Prednisolon oral, Mycophenolat, Alitretinoin und Leflunomid wurden ebenfalls bei einzelnen Patienten eingesetzt. Die vorliegende Registerauswertung gibt wichtige Hinweise zur derzeitigen Versorgung von Erwachsenen mit schwerer Neurodermitis in Deutschland, dokumentiert die hohe Erkrankungslast, den Nutzen vorhandener Therapien und den Bedarf an weiteren, effektiven und in der Langzeitanwendung sicheren Therapieoptionen. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  4. Kommunikation mit Mitarbeitern

    NASA Astrophysics Data System (ADS)

    Spychala, Anne; Fleischmann, Jürgen

    Kommunikation ist der Austausch von Nachrichten und Informationen zwischen Mitarbeitern eines Unternehmens (O'Hair et al. 1997). Dieser Austausch kann persönlich, aber z.B. auch per Telefon, E-Mail oder durch Computersysteme erfolgen. In diesem Kapitel betrachten wir die persönliche Kommunikation zwischen Vorgesetzten und Mitarbeitern. Zur persönlichen Kommunikation mit Mitarbeitern zählen sowohl formelle Gespräche mit Mitarbeitern als auch eher informelle Gespräche zwischen Tür und Angel. Die Gespräche können dabei mit einzelnen Mitarbeitern (z.B. jährliches Mitarbeitergespräch) oder mit Gruppen von Mitarbeitern (z.B. regelmäßige Projekt- oder Teambesprechungen) stattfinden.

  5. De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes

    PubMed Central

    Lopes, Matheus Rodrigues; Pereira, João Kleber Novais; de Melo Campos, Paula; Machado-Neto, João Agostinho; Traina, Fabiola; Saad, Sara T. Olalla; Favaro, Patricia

    2017-01-01

    The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu. PMID:28084439

  6. The applicability of the WHO classification in paediatric AML. A NOPHO-AML study.

    PubMed

    Sandahl, Julie D; Kjeldsen, Eigil; Abrahamsson, Jonas; Ha, Shau-Yin; Heldrup, Jesper; Jahnukainen, Kirsi; Jónsson, Ólafur G; Lausen, Birgitte; Palle, Josefine; Zeller, Bernward; Forestier, Erik; Hasle, Henrik

    2015-06-01

    The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18 years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n = 14) had significantly poorer outcome than del(7q) (n = 11); 5-year event-free survival 26% vs. 67%, (P = 0·02), and 5-year overall survival 51% vs. 90%, (P = 0·04). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n = 280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML.

  7. De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes.

    PubMed

    Lopes, Matheus Rodrigues; Pereira, João Kleber Novais; de Melo Campos, Paula; Machado-Neto, João Agostinho; Traina, Fabiola; Saad, Sara T Olalla; Favaro, Patricia

    2017-01-13

    The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu.

  8. Pediatric AML: From Biology to Clinical Management.

    PubMed

    de Rooij, Jasmijn D E; Zwaan, C Michel; van den Heuvel-Eibrink, Marry

    2015-01-09

    Pediatric acute myeloid leukemia (AML) represents 15%-20% of all pediatric acute leukemias. Survival rates have increased over the past few decades to ~70%, due to improved supportive care, optimized risk stratification and intensified chemotherapy. In most children, AML presents as a de novo entity, but in a minority, it is a secondary malignancy. The diagnostic classification of pediatric AML includes a combination of morphology, cytochemistry, immunophenotyping and molecular genetics. Outcome is mainly dependent on the initial response to treatment and molecular and cytogenetic aberrations. Treatment consists of a combination of intensive anthracycline- and cytarabine-containing chemotherapy and stem cell transplantation in selected genetic high-risk cases or slow responders. In general, ~30% of all pediatric AML patients will suffer from relapse, whereas 5%-10% of the patients will die due to disease complications or the side-effects of the treatment. Targeted therapy may enhance anti-leukemic efficacy and minimize treatment-related morbidity and mortality, but requires detailed knowledge of the genetic abnormalities and aberrant pathways involved in leukemogenesis. These efforts towards future personalized therapy in a rare disease, such as pediatric AML, require intensive international collaboration in order to enhance the survival rates of pediatric AML, while aiming to reduce long-term toxicity.

  9. Prä- und perioperative Aspekte der Versorgung dermatochirurgischer Patienten.

    PubMed

    Müller, Cornelia S L; Hubner, Wakiko; Thieme-Ruffing, Sigrid; Pföhler, Claudia; Vogt, Thomas; Volk, Thomas; Gärtner, Barbara C; Bialas, Patric

    2017-02-01

    Die Dermatochirurgie nimmt hinsichtlich vieler Punkte eine Sonderstellung unter den operativen Fächern ein. Hierzu gehört in erster Linie die Tatsache, dass bis auf wenige Ausnahmen fast alle Eingriffe traditionell in Lokal- bzw. Regionalanästhesie und oft auch in räumlich-infrastruktureller Trennung von den großen Zentral-Operationssälen stattfinden können. Die peri- und postoperative Überwachung obliegt dabei dem dermatochirurgischen Operationsteam. Das sui generis kleinere OP-Team hat somit eine ganze Reihe perioperativer Notwendigkeiten zu beachten, um die sich in den "großen" chirurgischen Fächern eine Vielzahl verschiedener beteiligter Fachgruppen gemeinsam kümmern. Hierzu gehören neben Hygieneaspekten, Kenntnissen in der Überwachung der Patienten sowie dem Aspekt der surgical site infections auch Fragen zur postoperativen Schmerztherapie sowie detailliertes pharmakologisches Wissen über die zur Anwendung kommenden Lokalanästhetika und das Handling der damit assoziierten toxischen und allergischen Reaktionen. Eine interdisziplinäre Zusammenarbeit und Verantwortung für den Patienten ist notwendig und erfordert die Erarbeitung und Umsetzung qualitätsorientierter und evidenzbasierter Handlungsanweisungen, die im dermatochirurgischen OP-Setting meist weit über das eigentliche Fach hinausgehen. Ziel dieses Weiterbildungsartikels soll die komprimierte Darstellung der genannten fachübergreifenden Standpunkte bezüglich der wichtigsten perioperativen Aspekte sein. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  10. MPD work at MIT

    NASA Technical Reports Server (NTRS)

    Martinez-Sanchez, Manuel

    1991-01-01

    MPD work at MIT is presented in the form of the view-graphs. The following subject areas are covered: the MIT program, its goals, achievements, and roadblocks; quasi one-dimensional modeling; two-dimensional modeling - transport effects and Hall effect; microscopic instabilities in MPD flows and modified two stream instability; electrothermal stability theory; separation of onset and anode depletion; exit plane spectroscopic measurements; phenomena of onset as performance limiter; explanations of onset; geometry effects on onset; onset at full ionization and its consequences; relationship to anode depletion; summary on self-field MPD; applied field MPD - the logical growth path; the case for AF; the challenges of AF MPD; and recommendations.

  11. Rational Combinations of Targeted Agents in AML

    PubMed Central

    Bose, Prithviraj; Grant, Steven

    2015-01-01

    Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many “synthetic lethal” strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies. PMID:26113989

  12. Abdichtungen mit Bitumenbahnen

    NASA Astrophysics Data System (ADS)

    Rahn, Axel C.; Unger, Wolfram

    Das Werk Bauwerksabdichtung von Karl Lufsky, im allgemeinen Sprachgebrauch auch Der Lufsky genannt, war immer das Standardwerk für Flächenabdichtungen mit Bitumenwerkstoffen. Karl Lufsky war erst Mitarbeiter des Geschäftsführers Otto Latendorf der 1924 in Berlin gegründeten Firma ARIDO Abdichtungs-GmbH und später ihr Geschäftsführer [8.1]. Eine Baustelle war seit 1950 der Keller der neuen Sowjetischen Botschaft Unter den Linden. Eines Tages sprach dort einer der russischen Ingenieur-Offiziere Otto Latendorf an und fragte ihn, ob er wohl eine schriftliche Zusammenfassung aller technischen Probleme der bituminösen Bauwerksabdichtung für ihn verfassen könnte. Mit dieser Schrift würde er sich dann zu seinem Abschlussexamen in Moskau melden. Vergüten wollte er den Arbeitsaufwand mit Lebensmittellieferungen. Otto Latendorf willigte ein und machte sich gemeinsam mit Karl Lufsky an die Arbeit. Dies war offensichtlich der Impuls für Karl Lufsky, einige Zeit später im Leipziger Teubner Verlag die erste Auflage des Buchs "Bauwerksabdichtungen“ herauszugeben, womit der Grundstein gelegt wurde, aus einer "Moskauer Examensarbeit“ in den letzten 50 Jahren ein bedeutendes Fachbuch zu machen.

  13. CBFβ is critical for AML1-ETO and TEL-AML1 activity

    PubMed Central

    Roudaia, Liya; Cheney, Matthew D.; Manuylova, Ekaterina; Chen, Wei; Morrow, Michelle; Park, Sangho; Lee, Chung-Tsai; Kaur, Prabhjot; Williams, Owen

    2009-01-01

    AML1-ETO and TEL-AML1 are chimeric proteins resulting from the t(8;21)(q22;q22) in acute myeloid leukemia, and the t(12;21)(p13;q22) in pre-B-cell leukemia, respectively. The Runt domain of AML1 in both proteins mediates DNA binding and heterodimerization with the core binding factor β (CBFβ) subunit. To determine whether CBFβ is required for AML1-ETO and TEL-AML1 activity, we introduced amino acid substitutions into the Runt domain that disrupt heterodimerization with CBFβ but not DNA binding. We show that CBFβ contributes to AML1-ETO's inhibition of granulocyte differentiation, is essential for its ability to enhance the clonogenic potential of primary mouse bone marrow cells, and is indispensable for its cooperativity with the activated receptor tyrosine kinase TEL-PDGFβR in generating acute myeloid leukemia in mice. Similarly, CBFβ is essential for TEL-AML1's ability to promote self-renewal of B cell precursors in vitro. These studies validate the Runt domain/CBFβ interaction as a therapeutic target in core binding factor leukemias. PMID:19179469

  14. AML in 2016: Where we are now?

    PubMed

    Rowe, Jacob M

    2016-12-01

    A high relapse rate for patients with acute myeloid leukemia (AML) is still a major barrier to the long-term survival of these patients. Nevertheless, considerable progress has been made both in the biology and therapy of the disease. Specifically, progress has been made in the areas of integrated genomic analysis for prognosis, the widening application of minimal residual disease (MRD) monitoring in clinical practice, the development of new agents, and the increasing use of drugs, such as IDH and FLT3 inhibitors, as a bridge to transplant. Continued progress and inquiry into these and other areas are essential to improve the survival outcome for adult patients with AML.

  15. Prognostic Factors in Childhood Leukemia (ALL or AML)

    MedlinePlus

    ... Diagnosis, and Types Prognostic Factors in Childhood Leukemia (ALL or AML) Certain factors that can affect a ... myelogenous leukemia (AML). Prognostic factors for children with ALL Children with ALL are often divided into risk ...

  16. The chimeric genes AML1/DS1 and AML1/EAP inhibit AML1B activation at the CSF1R promoter, but only AML1/MDS1 has tumor-promoter properties

    SciTech Connect

    Zent, C.S.; Matheiu, C.; Rowley, J.D.

    1996-02-06

    The (3;21)(q26;q22) translocation associated with treatment-related myelodysplastic syndrome, treatment-related acute myeloid leukemia, and blast crisis of chronic myeloid leukemia results in the expression of the chimeric genes AML1/EAP, AML1MDS1, and AML1/EVI1. AML1 (CBFA2), which codes for the {alpha} subunit of the heterodimeric transcription factor CBF, is also involved in the t(8;21), and the gene coding for the {beta} subunit (CBFB) is involved in the inv(16). These are two of the most common recurring chromosomal rearrangements in acute myeloid leukemia. CBF corresponds to the murine Pebp2 factor, and CBF binding sites are found in a number of eukaryotic and viral enhancers and promoters. We studied the effects of AML1/EAP and AML1/MDS1 at the AML1 binding site of the CSF1R (macrophage-colony-stimulating factor receptor gene) promoter by using reporter gene assays, and we analyzed the consequences of the expression of both chimeric proteins in an embryonic rat fibroblast cell line (Rat1A) in culture and after injection into athymic nude mice. Unlike AML1, which is an activator of the CSF1R promoter, the chimeric proteins did not transactivate the CSF1R promoter site but acted as inhibitors of AMLI (CBFA2). AML1/EAP and AML1/MDS1 expressed in adherent Rat1A cells decreased contact inhibition of growth, and expression of AML1/MDS1 was associated with acquisition of the ability to grow in suspension culture. Expression of AML1/MDS1 increased the tumorigenicity of Rat1A cells injected into athymic nude mice, whereas AML1/EAP expression provented tumor growth. These results suggest that expression of AML1/MDS1 can interfere with normal AML1 function, and that AML1/MDS1 has tumor-promoting properties in an embryonic rat fibroblast cell line. 26 refs., 5 figs.

  17. The role of the proteasome in AML

    PubMed Central

    Csizmar, C M; Kim, D-H; Sachs, Z

    2016-01-01

    Acute myeloid leukemia (AML) is deadly hematologic malignancy. Despite a well-characterized genetic and molecular landscape, targeted therapies for AML have failed to significantly improve clinical outcomes. Over the past decade, proteasome inhibition has been demonstrated to be an effective therapeutic strategy in several hematologic malignancies. Proteasome inhibitors, such as bortezomib and carfilzomib, have become mainstays of treatment for multiple myeloma and mantle cell lymphoma. In light of this success, there has been a surge of literature exploring both the role of the proteasome and the effects of proteasome inhibition in AML. Pre-clinical studies have demonstrated that proteasome inhibition disrupts proliferative cell signaling pathways, exhibits cytotoxic synergism with other chemotherapeutics and induces autophagy of cancer-related proteins. Meanwhile, clinical trials incorporating bortezomib into combination chemotherapy regimens have reported a range of responses in AML patients, with complete remission rates >80% in some cases. Taken together, this preclinical and clinical evidence suggests that inhibition of the proteasome may be efficacious in this disease. In an effort to focus further investigation into this area, these recent studies and their findings are reviewed here. PMID:27911437

  18. Treatment of older patients with AML.

    PubMed

    Büchner, Thomas; Berdel, Wolfgang E; Wörmann, Bernhard; Schoch, Claudia; Haferlach, Torsten; Schnittger, Susanne; Kern, Wolfgang; Aul, Carlo; Lengfelder, Eva; Schumacher, Andrea; Reichle, Albrecht; Staib, Peter; Balleisen, Leopold; Eimermacher, Hartmut; Grüneisen, Andreas; Rasche, Herbert; Sauerland, Maria Cristina; Heinecke, Achim; Mesters, Rolf M; Serve, Hubert L; Kienast, Joachim; Hiddemann, Wolfgang

    2005-11-01

    Undertreatment of the older patients with AML can explain, in part, their inferior outcome when compared with that in younger patients. In analogy to the benefit of patients under the age of 60 years from high-dose AraC there are dosage related therapeutic effects in the patients over 60 years in particular for daunorubicin in the induction treatment, and for maintenance versus no maintenance in the post-remission treatment. Utilizing these effects can partly overcome the mostly unfavorable disease biology in older age AML, whereas the role of risk factors involved is not completely understood and the concept of dose-response needs to be requestioned. We recommend an adequate dosage of 60 mg/(m2day) daunorubicin for 3 days in a combination with standard dose AraC and 6-thioguanine given for induction and consolidation and followed by a prolonged monthly maintenance chemotherapy. Further improvements in supportive care may help delivering additional anti-leukemic cytotoxicity. As a novel approach, reduced toxicity preparative regimens may open up allogeneic transplantation for older patients with AML. Other new options like MDR modulators, antibody targeted therapies and tyrosine kinase inhibitors are under clinical investigation. A questionnaire study in patients with AML showed that according to patients' self-assessment intensive and prolonged treatment did not result in decreasing quality of life. This finding did not vary by age under or above 60 years. Given the actual median age in this disease being more than 60 years the adequate management of older age AML remains as the major challenge.

  19. Update on rational targeted therapy in AML.

    PubMed

    Shafer, Danielle; Grant, Steven

    2016-07-01

    Acute myeloid leukemia (AML) remains a challenge to both patients and clinicians. Despite improvements in our understanding of the disease, treatment has changed minimally and outcomes remain poor for the majority of patients. Within the last decade, there have been an increasing number of potential targets and pathways identified for development in AML. The classes of agents described in this review include but are not limited to epigenetic modifiers such as IDH inhibitors, BET inhibitors, and HDAC inhibitors as well as cell cycle and signaling inhibitors such as Aurora kinase inhibitors and CDK inhibitors. While the developments are encouraging, it is unlikely that targeting a single pathway will result in long-term disease control. Accordingly, we will also highlight potential rational partners for the novel agents described herein.

  20. Update on rational targeted therapy in AML

    PubMed Central

    Shafer, Danielle; Grant, Steven

    2016-01-01

    Acute myeloid leukemia (AML) remains a challenge to both patients and clinicians. Despite improvements in our understanding of the disease, treatment has changed minimally and outcomes remain poor for the majority of patients. Within the last decade, there have been an increasing number of potential targets and pathways identified for development in AML. The classes of agents described in this review include but are not limited to epigenetic modifiers such as IDH inhibitors, BET inhibitors, and HDAC inhibitors as well as cell cycle and signaling inhibitors such as Aurora kinase inhibitors and CDK inhibitors. While the developments are encouraging, it is unlikely that targeting a single pathway will result in long-term disease control. Accordingly, we will also highlight potential rational partners for the novel agents described herein. PMID:26972558

  1. Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML.

    PubMed

    Malani, D; Murumägi, A; Yadav, B; Kontro, M; Eldfors, S; Kumar, A; Karjalainen, R; Majumder, M M; Ojamies, P; Pemovska, T; Wennerberg, K; Heckman, C; Porkka, K; Wolf, M; Aittokallio, T; Kallioniemi, O

    2016-12-02

    We sought to identify drugs that could counteract cytarabine resistance in acute myeloid leukemia (AML) by generating eight resistant variants from MOLM-13 and SHI-1 AML cell lines by long-term drug treatment. These cells were compared with 66 ex vivo chemorefractory samples from cytarabine-treated AML patients. The models and patient cells were subjected to genomic and transcriptomic profiling and high-throughput testing with 250 emerging and clinical oncology compounds. Genomic profiling uncovered deletion of the deoxycytidine kinase (DCK) gene in both MOLM-13- and SHI-1-derived cytarabine-resistant variants and in an AML patient sample. Cytarabine-resistant SHI-1 variants and a subset of chemorefractory AML patient samples showed increased sensitivity to glucocorticoids that are often used in treatment of lymphoid leukemia but not AML. Paired samples taken from AML patients before treatment and at relapse also showed acquisition of glucocorticoid sensitivity. Enhanced glucocorticoid sensitivity was only seen in AML patient samples that were negative for the FLT3 mutation (P=0.0006). Our study shows that development of cytarabine resistance is associated with increased sensitivity to glucocorticoids in a subset of AML, suggesting a new therapeutic strategy that should be explored in a clinical trial of chemorefractory AML patients carrying wild-type FLT3.Leukemia advance online publication, 2 December 2016; doi:10.1038/leu.2016.314.

  2. [Radiation-induced and therapy-related AML/MDS].

    PubMed

    Inaba, Toshiya

    2009-10-01

    Radiation induced acute myeloid leukemia (AML) was recognized a century ago, soon after mankind found radiation. Atomic bomb survivors developed de novo AML with relatively short latency with very high frequency. By contrast, excess occurrence of myelodysplastic syndrome (MDS) as well as solid tumors was found decades late. This difference may be due to etiology that many de novo AML patients harbor chimeric leukemogenic genes caused by chromosomal translocations, while MDS patients rarely carry chimeras. In addition, epigenetic change would play important roles. Therapy related leukemia is mainly caused by topoisomerase II inhibitors that cause de novo AML with an 11q23 translocation or by alkyrating agents that induce MDS/AML with an AML1 point mutation and monosomy 7.

  3. Blastic leukaemias (AML): a biologist's view.

    PubMed

    Cáceres-Cortés, Julio Roberto

    2013-05-01

    Acute myeloblastic leukaemia is characterised by the extreme clonal proliferation of haematopoietic precursor cells with abnormal or arrested differentiation. Chemotherapy of acute leukaemia is channelled towards the reduction and eradication of leukaemic cells. However, relapse is generally assumed to occur in residual host cells, which are refractory to or elude therapy. The cancer stem cell hypothesis has gained considerable importance in recent years and could interpret this behaviour. This persuasive theory states that cells within a tumour are organised in a hierarchy similar to that of normal tissues and are maintained by a small subset of cells responsible for tumour dormancy. These cells, defined as 'tumour initiating cells' (TICs), possess several properties of normal tissue stem cells. Recently, the TICs associated with AML have been shown to comprise distinct, hierarchically arranged classes similar to those observed for haematopoietic stem cells. We know now that the growth and survival of blasts in AML are driven by the same growth factors that stimulate normal cells. Furthermore, direct evidence of the role of membrane stem cell factor and its receptor c-Kit in cell-cell interactions and cell survival in primary AML blasts have been provided, defining the importance of juxtacrine stimulation. Inhibition of c-Kit signalling induces combinations of cell death: autophagy (compensatory mechanism towards survival) and apoptosis. While recent work confirmed that c-Kit inhibitors reduce cancer cell proliferation, it also demonstrated that future inappropriate prescriptions could cause normal tissue deterioration. The purpose of this paper was to review some of the salient features of leukaemic blasts in support of the proposal that research into neoplasia be increased. Rather than presenting the details of various studies, I have attempted to indicate general areas in which work has been done or is in progress. It is hoped that this survey of the subject

  4. New study reveals relatively few mutations in AML genomes - TCGA

    Cancer.gov

    Investigators for The Cancer Genome Atlas (TCGA) Research Network have detailed and broadly classified the genomic alterations that frequently underlie the development of acute myeloid leukemia (AML).

  5. Chemosensitizing AML cells by targeting bone marrow endothelial cells.

    PubMed

    Bosse, Raphael C; Wasserstrom, Briana; Meacham, Amy; Wise, Elizabeth; Drusbosky, Leylah; Walter, Glenn A; Chaplin, David J; Siemann, Dietmar W; Purich, Daniel L; Cogle, Christopher R

    2016-05-01

    Refractory disease is the greatest challenge in treating patients with acute myeloid leukemia (AML). Blood vessels may serve as sanctuary sites for AML. When AML cells were co-cultured with bone marrow endothelial cells (BMECs), a greater proportion of leukemia cells were in G0/G1. This led us to a strategy of targeting BMECs with tubulin-binding combretastatins, causing BMECs to lose their flat phenotype, degrade their cytoskeleton, cease growth, and impair migration despite unchanged BMEC viability and metabolism. Combretastatins also caused downregulation of BMEC adhesion molecules known to tether AML cells, including vascular cell adhesion molecule (VCAM)-1 and vascular endothelial (VE)-cadherin. When AML-BMEC co-cultures were treated with combretastatins, a significantly greater proportion of AML cells dislodged from BMECs and entered the G2/M cell cycle, suggesting enhanced susceptibility to cell cycle agents. Indeed, the combination of combretastatins and cytotoxic chemotherapy enhanced additive AML cell death. In vivo mice xenograft studies confirmed this finding by revealing complete AML regression after treatment with combretastatins and cytotoxic chemotherapy. Beyond highlighting the pathologic role of BMECs in the leukemia microenvironment as a protective reservoir of disease, these results support a new strategy for using vascular-targeting combretastatins in combination with cytotoxic chemotherapy to treat AML.

  6. Osteoblasts Protect AML Cells from SDF-1-Induced Apoptosis

    PubMed Central

    Kremer, Kimberly N.; Dudakovic, Amel; McGee-Lawrence, Meghan E.; Philips, Rachael L.; Hess, Allan D.; Smith, B. Douglas; van Wijnen, Andre J.; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; Hedin, Karen E.

    2014-01-01

    The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF-1 naturally present in that location. In co-culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF-1-induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W-20-17, mediated this protection via a cell contact-independent mechanism. In contrast, bone marrow-derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4-dependent mechanism and failed to protect AML cells from exogenously added SDF-1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF-1-driven apoptotic pathway of CXCR4-expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF-1-induced apoptosis of AML cells residing within the bone marrow microenvironment. PMID:24851270

  7. Aberrant AML1 gene expression in the diagnosis of childhood leukemias not characterized by AML1-involved cytogenetic abnormalities.

    PubMed

    Adamaki, Maria; Vlahopoulos, Spiros; Lambrou, George I; Papavassiliou, Athanasios G; Moschovi, Maria

    2017-03-01

    The AML1 ( acute myeloid leukemia 1) gene, a necessary prerequisite of embryonic hematopoiesis and a critical regulator of normal hematopoietic development, is one of the most frequently mutated genes in human leukemia, involving over 50 chromosome translocations and over 20 partner genes. In the few existing studies investigating AML1 gene expression in childhood leukemias, aberrant upregulation seems to specifically associate with AML1 translocations and amplifications. The aim of this study was to determine whether overexpression also extends to other leukemic subtypes than the ones karyotypically involving AML1. We use quantitative real-time polymerase chain reaction methodology to investigate gene expression in 100 children with acute leukemias and compare them to those of healthy controls. We show that in childhood acute lymphoblastic leukemia, AML1 gene overexpression is associated with a variety of leukemic subtypes, both immunophenotypically and cytogenetically. Statistically significantly higher transcripts of the gene were detected in the acute lymphoblastic leukemia group as compared to the acute myeloid leukemia group, where AML1 overexpression appeared to associate with cytogenetic abnormalities additional to those that engage the AML1 gene, or that are reported as showing a "normal" karyotype. Collectively, our study shows that AML1 gene overexpression characterizes a broader range of leukemic subtypes than previously thought, including various maturation stages of B-cell acute lymphoblastic leukemia and cytogenetic types additional to those involving the AML1 gene.

  8. MIT-CSR XIS Project

    NASA Technical Reports Server (NTRS)

    1998-01-01

    This report outlines the proposers' progress toward MIT's contribution to the X-Ray Imaging Spectrometer (XIS) experiment on the Japanese ASTRO-E mission. The report discusses electrical system design, mechanical system design, and ground support equipment.

  9. Advanced Manned Launch System (AMLS) study

    NASA Astrophysics Data System (ADS)

    Ehrlich, Carl F., Jr.; Potts, Jack; Brown, Jerry; Schell, Ken; Manley, Mary; Chen, Irving; Earhart, Richard; Urrutia, Chuck; Randolph, Ray; Morris, Jim

    1992-09-01

    To assure national leadership in space operations and exploration in the future, NASA must be able to provide cost effective and operationally efficient space transportation. Several NASA studies and the joint NASA/DoD Space Transportation Architecture Studies (STAS) have shown the need for a multi-vehicle space transportation system with designs driven by enhanced operations and low costs. NASA is currently studying an advanced manned launch system (AMLS) approach to transport crew and cargo to the Space Station Freedom. Several single and multiple stage systems from air-breathing to all-rocket concepts are being examined in a series of studies potential replacements for the Space Shuttle launch system in the 2000-2010 time frame. Rockwell International Corporation, under contract to the NASA Langley Research Center, has analyzed a two-stage all-rocket concept to determine whether this class of vehicles is appropriate for the AMLS function. The results of the pre-phase A study are discussed.

  10. Advanced Manned Launch System (AMLS) study

    NASA Technical Reports Server (NTRS)

    Ehrlich, Carl F., Jr.; Potts, Jack; Brown, Jerry; Schell, Ken; Manley, Mary; Chen, Irving; Earhart, Richard; Urrutia, Chuck; Randolph, Ray; Morris, Jim

    1992-01-01

    To assure national leadership in space operations and exploration in the future, NASA must be able to provide cost effective and operationally efficient space transportation. Several NASA studies and the joint NASA/DoD Space Transportation Architecture Studies (STAS) have shown the need for a multi-vehicle space transportation system with designs driven by enhanced operations and low costs. NASA is currently studying an advanced manned launch system (AMLS) approach to transport crew and cargo to the Space Station Freedom. Several single and multiple stage systems from air-breathing to all-rocket concepts are being examined in a series of studies potential replacements for the Space Shuttle launch system in the 2000-2010 time frame. Rockwell International Corporation, under contract to the NASA Langley Research Center, has analyzed a two-stage all-rocket concept to determine whether this class of vehicles is appropriate for the AMLS function. The results of the pre-phase A study are discussed.

  11. MIT research in telerobotics

    NASA Technical Reports Server (NTRS)

    Sheridan, T. B.

    1987-01-01

    Ongoing MIT research in telerobotics (vehicles capable of some autonomous sensing and manipulating, having some remote supervisory control by people) and teleoperation (vehicles for sensing and manipulating which are fully controlled remotely by people) is discussed. The current efforts mix human and artificial intelligence/control. The idea of adjustable impedance at either end of pure master-slave teleoperation, and simultaneous coordinated control of teleoperator/telerobotic systems which have more than six degrees of freedom (e.g., a combined vehicle and arm, each with five or six DOF) are discussed. A new cable-controlled parallel link arm which offers many advantages over conventional arms for space is briefly described. Predictor displays to compensate for time delay in teleoperator loops, the use of state estimation to help human control decisions in space, and ongoing research in supervisory command language are covered. Finally, efforts to build a human flyable real-time dynamic computer-graphic telerobot simulator are described. These projects represent most, but not all, of the telerobotics research in our laboratory, supported by JPL, NASA Ames and NOAA.

  12. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation.

    PubMed Central

    Meyers, S; Lenny, N; Hiebert, S W

    1995-01-01

    The AML-1/CBF beta transcription factor complex is targeted by both the t(8;21) and the inv(16) chromosomal alterations, which are frequently observed in acute myelogenous leukemia. AML-1 is a site-specific DNA-binding protein that recognizes the enhancer core motif TGTGGT. The t(8;21) translocation fuses the first 177 amino acids of AML-1 to MTG8 (also known as ETO), generating a chimeric protein that retains the DNA-binding domain of AML-1. Analysis of endogenous AML-1 DNA-binding complexes suggested the presence of at least two AML-1 isoforms. Accordingly, we screened a human B-cell cDNA library and isolated a larger, potentially alternatively spliced, form of AML1, termed AML1B. AML-1B is a protein of 53 kDa that binds to a consensus AML-1-binding site and complexes with CBF beta. Subcellular fractionation experiments demonstrated that both AML-1 and AML-1/ETO are efficiently extracted from the nucleus under ionic conditions but that AML-1B is localized to a salt-resistant nuclear compartment. Analysis of the transcriptional activities of AML-1, AML-1B, and AML-1/ETO demonstrated that only AML-1B activates transcription from the T-cell receptor beta enhancer. Mixing experiments indicated that AML-1/ETO can efficiently block AML-1B-dependent transcriptional activation, suggesting that the t(8;21) translocation creates a dominant interfering protein. PMID:7891692

  13. Nassi-Schneiderman Diagram in HTML Based on AML

    ERIC Educational Resources Information Center

    Menyhárt, László

    2013-01-01

    In an earlier work I defined an extension of XML called Algorithm Markup Language (AML) for easy and understandable coding in an IDE which supports XML editing (e.g. NetBeans). The AML extension contains annotations and native language (English or Hungarian) tag names used when coding our algorithm. This paper presents a drawing tool with which…

  14. [AML treatment strategy based on cytogenetic abnormalities and somatic mutations].

    PubMed

    Imai, Yoichi

    2015-10-01

    In addition to morphological and histocytochemical analyses of acute myeloid leukemia (AML), data on cytogenetic abnormalities and somatic mutations are used for classification of AML. The risk stratification based on these examinations facilitates determining the treatment strategy for AML. Cytogenetic risk category definitions by the Southwest Oncology Group (SWOG), Cancer and Leukemia Group B (CALGB), and The Medical Research Council (MRC) classify AML patients into favorable, intermediate, and adverse groups. Approximately 80% of patients in the intermediate group have a normal karyotype and the importance of molecular genetic analyses in these patients is increasing. Somatic mutations of NPM1, CEBPA, and FLT3 are known to be related to the prognosis of AML patients. The European LeukemiaNet (ELN) introduced risk stratification for AML patients based on cytogenetic abnormalities and NPM1, CEBPA, and FLT3 mutations. This risk stratification can be used to select only chemotherapy or chemotherapy with allogeneic hematopoietic stem cell transplantation as consolidation therapy for individual AML patients. Development of molecular targeted therapies against FLT3 or IDH mutations is in progress and these novel therapies are expected to contribute to improving the prognosis of AML patients.

  15. MIT's interferometer CST testbed

    NASA Technical Reports Server (NTRS)

    Hyde, Tupper; Kim, ED; Anderson, Eric; Blackwood, Gary; Lublin, Leonard

    1990-01-01

    The MIT Space Engineering Research Center (SERC) has developed a controlled structures technology (CST) testbed based on one design for a space-based optical interferometer. The role of the testbed is to provide a versatile platform for experimental investigation and discovery of CST approaches. In particular, it will serve as the focus for experimental verification of CSI methodologies and control strategies at SERC. The testbed program has an emphasis on experimental CST--incorporating a broad suite of actuators and sensors, active struts, system identification, passive damping, active mirror mounts, and precision component characterization. The SERC testbed represents a one-tenth scaled version of an optical interferometer concept based on an inherently rigid tetrahedral configuration with collecting apertures on one face. The testbed consists of six 3.5 meter long truss legs joined at four vertices and is suspended with attachment points at three vertices. Each aluminum leg has a 0.2 m by 0.2 m by 0.25 m triangular cross-section. The structure has a first flexible mode at 31 Hz and has over 50 global modes below 200 Hz. The stiff tetrahedral design differs from similar testbeds (such as the JPL Phase B) in that the structural topology is closed. The tetrahedral design minimizes structural deflections at the vertices (site of optical components for maximum baseline) resulting in reduced stroke requirements for isolation and pointing of optics. Typical total light path length stability goals are on the order of lambda/20, with a wavelength of light, lambda, of roughly 500 nanometers. It is expected that active structural control will be necessary to achieve this goal in the presence of disturbances.

  16. How I treat FLT3-mutated AML

    PubMed Central

    Pratz, Keith W.

    2017-01-01

    FLT3-mutated acute myeloid leukemia (AML), despite not being recognized as a distinct entity in the World Health Organization (WHO) classification system, is readily recognized as a particular challenge by clinical specialists who treat acute leukemia. This is especially true with regards to the patients harboring the most common type of FLT3 mutation, the internal tandem duplication (FLT3-ITD) mutation. Here we present 4 patient cases from our institution and discuss how our management reflects what we have learned about this subtype of the disease. We also reflect on how we anticipate the management might change in the near future, with the emergence of clinically useful tyrosine kinase inhibitors. PMID:27872057

  17. Mitochondrial DNA damage by bleomycin induces AML cell death.

    PubMed

    Yeung, ManTek; Hurren, Rose; Nemr, Carine; Wang, Xiaoming; Hershenfeld, Samantha; Gronda, Marcela; Liyanage, Sanduni; Wu, Yan; Augustine, Jeevan; Lee, Eric A; Spagnuolo, Paul A; Southall, Noel; Chen, Catherine; Zheng, Wei; Jeyaraju, Danny V; Minden, Mark D; Laposa, Rebecca; Schimmer, Aaron D

    2015-06-01

    Mitochondria contain multiple copies of their own 16.6 kb circular genome. To explore the impact of mitochondrial DNA (mtDNA) damage on mitochondrial (mt) function and viability of AML cells, we screened a panel of DNA damaging chemotherapeutic agents to identify drugs that could damage mtDNA. We identified bleomycin as an agent that damaged mtDNA in AML cells at concentrations that induced cell death. Bleomycin also induced mtDNA damage in primary AML samples. Consistent with the observed mtDNA damage, bleomycin reduced mt mass and basal oxygen consumption in AML cells. We also demonstrated that the observed mtDNA damage was functionally important for bleomycin-induced cell death. Finally, bleomycin delayed tumor growth in xenograft mouse models of AML and anti-leukemic concentrations of the drug induced mtDNA damage in AML cells preferentially over normal lung tissue. Taken together, mtDNA-targeted therapy may be an effective strategy to target AML cells and bleomycin could be useful in the treatment of this disease.

  18. Microenvironmental hypoxia regulates FLT3 expression and biology in AML.

    PubMed

    Sironi, Silvia; Wagner, Michaela; Kuett, Alexander; Drolle, Heidrun; Polzer, Harald; Spiekermann, Karsten; Rieger, Christina; Fiegl, Michael

    2015-11-30

    Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase constitutively expressed by acute myeloid leukaemia (AML) blasts. In addition, 25% of AML patients harbour a FLT3-ITD mutation, associated with inferior outcome due to increased relapse rate. Relapse might be propagated by interactions between AML blasts and the bone marrow microenvironment. Besides cellular elements of the microenvironment (e.g. mesenchymal stromal cells), bone marrow hypoxia has emerged as an additional crucial component. Hence, effects of hypoxia on FLT3 expression and biology could provide novel insight into AML biology. Here we show that 25% of AML patients down-regulate FLT3 expression on blasts in response to in vitro hypoxia (1% O2), which was independent of its mutational state. While virtually no AML cell lines regulate FLT3 in response to hypoxia, the down-regulation could be observed in Ba/F3 cells stably transfected with different FLT3 mutants. Hypoxia-mediated down-regulation was specific for FLT3, reversible and proteasome-dependent; with FLT3 half-life being significantly shorter at hypoxia. Also, PI-3K inhibition could partially abrogate down-regulation of FLT3. Hypoxia-mediated down-regulation of FLT3 conferred resistance against cytarabine in vitro. In conclusion, FLT3 expression in AML is dependent on the oxygen partial pressure, but response to hypoxia differs.

  19. MIT Space Engineering Research Center

    NASA Technical Reports Server (NTRS)

    Crawley, Edward F.; Miller, David W.

    1990-01-01

    The Space Engineering Research Center (SERC) at MIT, started in Jul. 1988, has completed two years of research. The Center is approaching the operational phase of its first testbed, is midway through the construction of a second testbed, and is in the design phase of a third. We presently have seven participating faculty, four participating staff members, ten graduate students, and numerous undergraduates. This report reviews the testbed programs, individual graduate research, other SERC activities not funded by the Center, interaction with non-MIT organizations, and SERC milestones. Published papers made possible by SERC funding are included at the end of the report.

  20. When it comes to MRD, AML ≠ ALL.

    PubMed

    Paietta, Elisabeth

    2012-08-23

    Only the most specific main institutional affiliation is listed for Inside Blood authors, without indications of subdivisions, departments, parent institutions, or postal/geographic information. Please confirm or correct affiliation. Minimal residual disease (MRD) detection is standard of care in acute lymphoblastic leukemia (ALL),(1) but not acute myeloid leukemia (AML). In this issue of Blood, an AML trial by Loken and colleagues from the Children's Oncology Group (COG) retrospectively demonstrates clinical significance of MRD.(2) These data reaffirm that AML-MRD is unlike ALL-MRD.

  1. MIT January Operational Internship Experience

    NASA Technical Reports Server (NTRS)

    Bosanac, Natasha; DeVivero, Charlie; James, Jillian; Perez-Martinez, Carla; Pino, Wendy; Wang, Andrew; Willett, Ezekiel; Williams, Kwami

    2010-01-01

    This viewgraph presentation describes the MIT January Operational Internship Experience (JOIE) program. The topics include: 1) Landing and Recovery; 2) Transportation; 3) Shuttle Processing; 4) Constellation Processing; 5) External Tank; 6) Launch Pad; 7) Ground Operations; 8) Hypergolic Propellants; 9) Environmental; 10) Logistics; 11) Six Sigma; 12) Systems Engineering; and 13) Human Factors.

  2. Standard anatomical medullary locking (AML) versus tricalcium phosphate-coated AML femoral prostheses

    PubMed Central

    Johnston, D.W.C. (Bill); Davies, Donna M.; Beaupré, Lauren A.; Lavoie, Guy

    2001-01-01

    Objectives To compare the preliminary rate and amount of bony ingrowth and calcar resorption between patients receiving either a standard anatomical medullary locking (AML) or a tricalcium phosphate (TCP)-coated AML femoral prosthesis and to compare preliminary clinical results. Design A prospective, randomized, double-blind clinical trial. Setting An acute care tertiary institution. Patients Between January 1993 and March 1995, 92 patients underwent primary total hip arthroplasty (THA). They were randomized to 2 groups of 46 — a control group or a treatment group. Of the 46 subjects enrolled in each group, no significant differences were seen preoperatively with respect to age, sex, diagnosis, clinical and radiographic assessment. Seventy-one patients were followed up for 24 months. Interventions Insertion of either a standard AML femoral implant (control group) or a TCP-coated AML femoral implant (treatment group). Outcome measures The degree of hypertrophy, calcar atrophy and the number of spot welds on standard postoperative radiographs at 6, 12 and 24 months. Clinically, assessment according to the Société internationale de chirurgie orthopédique et de traumatologie (SICOT) scale and a 100-point visual analogue scale (VAS) for pain. Results There were no prosthetic stem revisions in either group at the 24-month follow-up. Radiographically, bony ingrowth was not significantly different in the TCP-coated stem, by χ2 analysis of the degree of hypertrophy and number of spot welds present. Also by χ2 analysis, the degree of calcar atrophy was not significantly different between groups. The mean VAS score for pain at 24 months was 12.5 for the control and 12.1 for the treatment group. No significant differences were seen in any of the clinical categories of the SICOT Scale over the 24-month interval. Conclusion The objective of TCP-coating — to increase the rate and amount of bony ingrowth while reducing the rate of calcar resorption in non-cemented THA

  3. Mouse models of human AML accurately predict chemotherapy response

    PubMed Central

    Zuber, Johannes; Radtke, Ina; Pardee, Timothy S.; Zhao, Zhen; Rappaport, Amy R.; Luo, Weijun; McCurrach, Mila E.; Yang, Miao-Miao; Dolan, M. Eileen; Kogan, Scott C.; Downing, James R.; Lowe, Scott W.

    2009-01-01

    The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients. PMID:19339691

  4. Mouse models of human AML accurately predict chemotherapy response.

    PubMed

    Zuber, Johannes; Radtke, Ina; Pardee, Timothy S; Zhao, Zhen; Rappaport, Amy R; Luo, Weijun; McCurrach, Mila E; Yang, Miao-Miao; Dolan, M Eileen; Kogan, Scott C; Downing, James R; Lowe, Scott W

    2009-04-01

    The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients.

  5. PU.1 downregulation in murine radiation-induced acute myeloid leukaemia (AML): from molecular mechanism to human AML

    PubMed Central

    Verbiest, Tom; Bouffler, Simon; Nutt, Stephen L.; Badie, Christophe

    2015-01-01

    The transcription factor PU.1, encoded by the murine Sfpi1 gene (SPI1 in humans), is a member of the Ets transcription factor family and plays a vital role in commitment and maturation of the myeloid and lymphoid lineages. Murine studies directly link primary acute myeloid leukaemia (AML) and decreased PU.1 expression in specifically modified strains. Similarly, a radiation-induced chromosome 2 deletion and subsequent Sfpi1 point mutation in the remaining allele lead to murine radiation-induced AML. Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the −14kb SPI1 upstream regulatory element were described previously in human primary AML, although they are rare events. Other mechanisms linked to PU.1 downregulation in human AML include TP53 deletion, FLT3-ITD mutation and the recurrent AML1-ETO [t(8;21)] and PML-RARA [t(15;17)] translocations. This review provides an up-to-date overview on our current understanding of the involvement of PU.1 in the initiation and development of radiation-induced AML, together with recommendations for future murine and human studies. PMID:25750172

  6. RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis

    PubMed Central

    Yan, Ming; Ahn, Eun-Young; Hiebert, Scott W.

    2009-01-01

    The 8;21 translocation, which involves the gene encoding the RUNX family DNA-binding transcription factor AML1 (RUNX1) on chromosome 21 and the ETO (MTG8) gene on chromosome 8, generates AML1-ETO fusion proteins. Previous analyses have demonstrated that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. More recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, from t(8;21) acute myeloid leukemia (AML) patient samples. AML1-ETO9a lacks the C-terminal NHR3 and NHR4 domains of AML1-ETO and is highly leukemogenic in the mouse model. Here, we report that the AML1 DNA-binding domain and the ETO NHR2-dimerization domain, but not the ETO NHR1 domain, are critical for the induction of AML by AML1-ETO9a. A region between NHR1 and NHR2 affects latency of leukemogenesis. These results provide valuable insight into further analysis of the molecular mechanism of t(8;21) in leukemogenesis. PMID:19036704

  7. Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML.

    PubMed

    Reichenbach, Frank; Wiedenmann, Cornelius; Schalk, Enrico; Becker, Diana; Funk, Kathrin; Scholz-Kreisel, Peter; Todt, Franziska; Wolleschak, Denise; Döhner, Konstanze; Marquardt, Jens U; Heidel, Florian; Edlich, Frank

    2017-08-15

    Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death.Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort.Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy.Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path." Clin Cancer Res; 23(16); 4805-16. ©2017 AACR. ©2017 American Association for Cancer Research.

  8. Educational Outreach at MIT PSFC

    NASA Astrophysics Data System (ADS)

    Rivenberg, P.; Thomas, P.; Censabella, V.

    2001-10-01

    At the MIT PSFC student and staff volunteers work together to increase the public's knowledge of fusion and plasma-related experiments. Seeking to generate excitement about science and engineering, the PSFC hosts a number of outreach activities throughout the year, including Middle and High School Outreach Days. Key to the success of these tours is the interactive ``C-Mod, Jr.," which helps students understand magnetic confinement in MIT's Alcator C-Mod tokamak. The PSFC also has an in-school science demonstration program on the theme of magnetism. As ``Mr. Magnet" Technical Supervisor Paul Thomas brings a truck-load of hands-on demonstrations to K-12 schools, challenging students to help him with experiments. While teaching fundamentals of magnetism and electricity he shows that science is fun for all, and that any student can have a career in science. This year he reached 77 schools -- 30,000 teachers and students. We have also collaborated with the MIT Museum to create an interactive plasma demonstration device which students and the general public can use to create plasmas from different gasses. Pinch and deflection magnets are moveable along the axis of the display, allowing investigation of the magnetic behavior of plasmas.

  9. Verantwortlicher Umgang mit Antibiotika: Notwendigkeit der Antibiotikareduktion in der Aknetherapie.

    PubMed

    Gollnick, Harald P M; Buer, Jan; Beissert, Stefan; Sunderkätter, Cord

    2016-12-01

    Der übermäßige oder unkritische weltweite Einsatz von Antibiotika in der Medizin hat die Ausbreitung von Antibiotikaresistenzen beschleunigt. In einigen Bereichen sind viele Antibiotika bei bakteriellen Infektionen, die zuvor noch gut auf antibakterielle Wirkstoffe reagierten, mittlerweile wirkungslos geworden. Dermatologen/Venerologen setzten orale und topische Antibiotika bei der Behandlung von Acne vulgaris routinemäßig ein, obwohl Akne weder eine infektiöse Erkrankung ist noch alleine durch das Propionibacterium getriggert wird. Vielmehr ist sie eine komplexe, chronische entzündliche Hauterkrankung, die durch verschiedene pathogenetische Faktoren wie follikuläre Hyperkeratose, erhöhter Sebumproduktion, bakterielle Proliferation und Entzündung zustande kommt. Folglich sollte eine erfolgreiche Therapie auf die Bekämpfung verschiedener pathogenetischer Faktoren und nicht nur auf die von Propionibacterium acnes abzielen. Daher wurden topische Retinoide und Benzoylperoxid als Mittel der ersten Wahl definiert. Monotherapien mit lokalen Antibiotika sollten insgesamt vermieden werden. Systemische Antibiotika der Tetrazyklin-Gruppe haben bei bestimmen Krankheitsstadien ihren Sinn, ihre Wirkung könnte aber eher auf der antientzündlichen als auf der antibiotischen Reaktion beruhen. Gesundheitsbehörden ermahnen alle Gesundheitsdienstleister, den Einsatz von Antibiotika einzuschränken. Das Nutzen-Risiko-Verhältnis muss bei der Entscheidung für oder gegen eine antibiotische Therapie bei einem einzelnen Patienten immer auch in Bezug auf das öffentliche Interesse am Erhalt der Wirksamkeit von Antibiotika abgewogen werden. Im Folgenden werden das aktuelle Krankheitskonzept zu Acne vulgaris und die sich daraus ableitenden Konsequenzen für den Einsatz von Antibiotika vorgestellt. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  10. Differential Analysis of Genetic, Epigenetic, and Cytogenetic Abnormalities in AML

    PubMed Central

    Islam, Mirazul

    2017-01-01

    Acute myeloid leukemia (AML) is a haematological malignancy characterized by the excessive proliferation of immature myeloid cells coupled with impaired differentiation. Many AML cases have been reported without any known cytogenetic abnormalities and carry no mutation in known AML-associated driver genes. In this study, 200 AML cases were selected from a publicly available cohort and differentially analyzed for genetic, epigenetic, and cytogenetic abnormalities. Three genes (FLT3, DNMT3A, and NPMc) are found to be predominantly mutated. We identified several aberrations to be associated with genome-wide methylation changes. These include Del (5q), T (15; 17), and NPMc mutations. Four aberrations—Del (5q), T (15; 17), T (9; 22), and T (9; 11)—are significantly associated with patient survival. Del (5q)-positive patients have an average survival of less than 1 year, whereas T (15; 17)-positive patients have a significantly better prognosis. Combining the methylation and mutation data reveals three distinct patient groups and four clusters of genes. We speculate that combined signatures have the better potential to be used for subclassification of AML, complementing cytogenetic signatures. A larger sample cohort and further investigation of the effects observed in this study are required to enable the clinical application of our patient classification aided by DNA methylation. PMID:28713819

  11. AML1/RUNX1 Phosphorylation by Cyclin-Dependent Kinases Regulates the Degradation of AML1/RUNX1 by the Anaphase-Promoting Complex‡

    PubMed Central

    Biggs, Joseph R.; Peterson, Luke F.; Zhang, Youhong; Kraft, Andrew S.; Zhang, Dong-Er

    2006-01-01

    AML1 (RUNX1) regulates hematopoiesis, angiogenesis, muscle function, and neurogenesis. Previous studies have shown that phosphorylation of AML1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of AML1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (CDKs) Cdk1 and Cdk2. Furthermore, these residues can be phosphorylated in vitro by purified Cdk1/cyclin B and Cdk2/cyclin A. Mutant AML1 protein which cannot be phosphorylated at these sites (AML1-4A) is more stable than wild-type AML1. AML-4A is resistant to degradation mediated by Cdc20, one of the substrate-targeting subunits of the anaphase-promoting complex (APC). However, Cdh1, another targeting subunit used by the APC, can mediate the degradation of AML1-4A. A phospho-mimic protein, AML1-4D, can be targeted by Cdc20 or Cdh1. These observations suggest that both Cdc20 and Cdh1 can target AML1 for degradation by the APC but that AML1 phosphorylation may affect degradation mediated by Cdc20-APC to a greater degree. PMID:17015473

  12. [Research advances of IDH gene mutation and AML].

    PubMed

    Sun, Ming-Dong; Zheng, Yong-Qin

    2014-10-01

    The isocitrate dehydrogenase (IDH) gene mutation has been recently found, which may be involved in the occurrence of leukemia. The incidence of IDH gene mutation in the patients with adult acute myeloid leukemia (AML) is high, especially in the AML patients with normal karyotype. Different subtype and molecular biology of IDH display a different effect on the AML prognosis. This gene mutation is related with treatment response, residual, recurrence of leukemia, and it could be a sign of test and a monitoring tool of minimal residual disease (MRD). The IDH gene mutation may be an index for predicting prognosis and guiding therapy. In this article, the research progress of IDH gene mutation and its correlation with acute myeloid leukemia, especially with the clinical characteristics,are reviewed.

  13. Controversies in treatment of AML: case-based discussion.

    PubMed

    Stock, Wendy

    2006-01-01

    Treatment of acute myeloid leukemia (AML) in older adults remains a tremendous challenge. Standard approaches to treatment have resulted in progression-free survival in only a small minority of patients with AML over the age of 60. Elucidation of the molecular genetic events that contribute to the pathogenesis of AML in older patients are providing insights into mechanisms of resistance. This knowledge is also providing new opportunities to begin to refine and direct novel therapies for these heterogeneous diseases. In this case-based review, prognostic factors for treatment outcome in older adults will be covered along with discussion of a risk-based approach to potential therapeutic options, ranging from palliative care to novel therapies and reduced-intensity allogenic transplant.

  14. Wetland development as a portion of AML reclamation

    SciTech Connect

    Joseph, W.L.

    1990-12-31

    The goal of Abandoned Mine Land (AML) reclamation is the development a multi-user land use that enhances the sites positive characteristics and eliminates negative ones. The AML program in the State of Kansas developed and reclaimed a large coal slurry disposal area by the use of wetlands. The main objective was to eliminate the acid mine drainage from the coal slurry and coarse fuel refuse areas but at the same time retain the wildlife habitat that had naturally developed on site. Selective flooding of various areas by the use of a series of small dams was the selected reclamation option. The project is now completed and is working as planned.

  15. Ten uncommon and unusual variants of renal angiomyolipoma (AML): radiologic-pathologic correlation.

    PubMed

    Schieda, N; Kielar, A Z; Al Dandan, O; McInnes, M D F; Flood, T A

    2015-02-01

    Classic (triphasic) renal angiomyolipoma (AML) is currently classified as a neoplasm of perivascular epithelioid cells. For diagnosis of AML, the use of thin-section non-contrast enhanced CT (NECT) improves diagnostic accuracy; however, identifying gross fat within a very small AML is challenging and often better performed with chemical-shift MRI. Although the presence of gross intra-tumoural fat is essentially diagnostic of AML; co-existing intra-tumoural fat and calcification may represent renal cell carcinoma (RCC). Differentiating AML from retroperitoneal sarcoma can be difficult when AML is large; the feeding vessel and claw signs are suggestive imaging findings. AML can haemorrhage, with intra-tumoural aneurysm size >5 mm a more specific predictor of future haemorrhage than tumor size >4 cm. Diagnosis of AML in the setting of acute haemorrhage is complex; comparison studies or follow-up imaging may be required. Not all AML contain gross fat and imaging features of AML without visible fat overlap with RCC; however, homogeneity, hyperdensity at NECT, low T2-weighted signal intensity and, microscopic fat are suggestive features. Patients with tuberous sclerosis often demonstrate a combination of classic and minimal fat AML, but are also at a slightly increased risk for RCC and should be imaged cautiously. Several rare pathological variants of AML exist including AML with epithelial cysts and epithelioid AML, which have distinct imaging characteristics. Classic AML, although benign, can be locally invasive and the rare epithelioid AML can be frankly malignant. The purpose of this review is to highlight the imaging manifestations of 10 uncommon and unusual variants of AML using pathological correlation.

  16. Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML.

    PubMed

    Schnittger, S; Kinkelin, U; Schoch, C; Heinecke, A; Haase, D; Haferlach, T; Büchner, T; Wörmann, B; Hiddemann, W; Griesinger, F

    2000-05-01

    Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid leukemia (AML) and recently, have also been reported for karyotypically normal AML. In order to test the incidence and prognostic importance of this molecular marker, we have analyzed eight cases of AML with trisomy 11 and 387 unselected consecutive cases with AML for partial duplications of the MLL gene. Patients with normal karyotypes and those with various chromosome aberrations were included. De novo as well as secondary leukemias including all FAB subtypes were analyzed. Performing a one-step RT-PCR with 35 cycles using an exon 9 forward primer and an exon 3 reverse primer partial tandem duplications of the MLL gene were demonstrated in 3/8 (37.5%) patients with trisomy 11. In addition, 13/387 (3.4%) of unselected cases revealed a tandem duplication. Ten of these 13 cases were cytogenetically normal, the other three cases had < or =2 additional chromosomal alterations. Sequencing of the RT-PCR products of all 16 positive cases revealed fusions of MLL exon 9/exon 3 (e9/e3) (six cases), e10/e3 (three cases), e11/e3 (four cases) or combinations of differentially spliced e10/e3 and e11/e3 (three cases) transcripts. The duplications were confirmed by genomic long range PCR and Southern blot hybridization. Twelve cases with the MLL duplication were de novo myeloid leukemia, one was a secondary AML after MDS, three were therapy-related AML (t-AML). Of the 16 MLL-duplication positive cases, seven were classified as FAB M2, two as M1, five as M4, one as M0, one as M5b. The mean age was 62.3 years for patients with MLL duplication vs 50.3 years for the control group. Of 15 adult patients, 12 received treatment. Of these, three were nonresponders, five had early relapse (< or =6 months), four relapsed between 7 and 12 months. Median survival and relapse-free interval of the MLL duplication positive group was significantly worse than those of an age-matched karyotypically

  17. An introduction to MIT mission

    NASA Astrophysics Data System (ADS)

    Liu, Y.; Wang, C.; Xu, J.

    2012-12-01

    MIT is a Chinese mission proposed to lunch following Double Star and KuaFu project. The mission targets at the material coupling of the earth's magnetosphere, ionosphere and thermosphere. Implementing the mission will further our understanding of the sun-earth system, characterize the impact of solar activity on Earth's space environment, improve the security for man-made spacecraft. The mission's science objectives include the mechanism and the origin of outflow oxygen ions and other related outstanding scientific questions. The mission plans four satellites: two of them have polar circular orbit at the lower attitude of 500km*1000km; the other two have other two have elliptical orbit of 6400km*43000km with angle 75°. These altitudes are the key regions for the acceleration of the outflow oxygen ions. The proposed payloads are particles detectors, field detectors, aurora and neutral imaging system. These payloads will measure the plasma compositions and the electromagnetic waves, therefore determine the key factors for the oxygen ions to gain energy and flow upward. In this paper, we report the detailed orbit, payload and the current status for the MIT mission.

  18. MLN0128, a novel mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML and AML stem/ progenitor cells

    PubMed Central

    Zeng, Zhihong; Wang, Rui-Yu; Qiu, Yi Hua; Mak, Duncan H.; Coombes, Kevin; Yoo, Suk Young; Zhang, Qi; Jessen, Katti; Liu, Yi; Rommel, Christian; Fruman, David A.; Kantarjian, Hagop M.; Kornblau, Steven M.; Andreeff, Michael; Konopleva, Marina

    2016-01-01

    mTOR activation leads to enhanced survival signaling in acute myeloid leukemia (AML) cells. The active-site mTOR inhibitors (asTORi) represent a promising new approach to targeting mTOR in AKT/mTOR signaling. MLN0128 is an orally-administered, second-generation asTORi, currently in clinical development. We examined the anti-leukemic effects and the mechanisms of action of MLN0128 in AML cell lines and primary samples, with a particular focus on its effect in AML stem/progenitor cells. MLN0128 inhibited cell proliferation and induced apoptosis in AML by attenuating the activity of mTOR complex 1 and 2. Using time-of-flight mass cytometry, we demonstrated that MLN0128 selectively targeted and functionally inhibited AML stem/progenitor cells with high AKT/mTOR signaling activity. Using the reverse-phase protein array technique, we measured expression and phosphorylation changes in response to MLN0128 in 151 proteins from 24 primary AML samples and identified several pro-survival pathways that antagonize MLN0128-induced cellular stress. A combined blockade of AKT/mTOR signaling and these pro-survival pathways facilitated AML cell killing. Our findings provide a rationale for the clinical use of MLN0128 to target AML and AML stem/progenitor cells, and support the use of combinatorial multi-targeted approaches in AML therapy. PMID:27391151

  19. MLN0128, a novel mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML and AML stem/ progenitor cells.

    PubMed

    Zeng, Zhihong; Wang, Rui-Yu; Qiu, Yi Hua; Mak, Duncan H; Coombes, Kevin; Yoo, Suk Young; Zhang, Qi; Jessen, Katti; Liu, Yi; Rommel, Christian; Fruman, David A; Kantarjian, Hagop M; Kornblau, Steven M; Andreeff, Michael; Konopleva, Marina

    2016-08-23

    mTOR activation leads to enhanced survival signaling in acute myeloid leukemia (AML) cells. The active-site mTOR inhibitors (asTORi) represent a promising new approach to targeting mTOR in AKT/mTOR signaling. MLN0128 is an orally-administered, second-generation asTORi, currently in clinical development. We examined the anti-leukemic effects and the mechanisms of action of MLN0128 in AML cell lines and primary samples, with a particular focus on its effect in AML stem/progenitor cells. MLN0128 inhibited cell proliferation and induced apoptosis in AML by attenuating the activity of mTOR complex 1 and 2. Using time-of-flight mass cytometry, we demonstrated that MLN0128 selectively targeted and functionally inhibited AML stem/progenitor cells with high AKT/mTOR signaling activity. Using the reverse-phase protein array technique, we measured expression and phosphorylation changes in response to MLN0128 in 151 proteins from 24 primary AML samples and identified several pro-survival pathways that antagonize MLN0128-induced cellular stress. A combined blockade of AKT/mTOR signaling and these pro-survival pathways facilitated AML cell killing. Our findings provide a rationale for the clinical use of MLN0128 to target AML and AML stem/progenitor cells, and support the use of combinatorial multi-targeted approaches in AML therapy.

  20. Inhibition of FLT3 in AML: a focus on sorafenib.

    PubMed

    Antar, A; Otrock, Z K; El-Cheikh, J; Kharfan-Dabaja, M A; Battipaglia, G; Mahfouz, R; Mohty, M; Bazarbachi, A

    2017-03-01

    FMS-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in AML. FLT3 is mutated in ~30% of patients with AML, either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or by a point mutation, usually involving the tyrosine kinase domain. Several FLT3 tyrosine kinase inhibitors are being evaluated in multiple studies aiming at improving outcomes. The most widely used is sorafenib, a potent multikinase inhibitor approved for hepatocellular carcinoma and renal cell carcinoma. Sorafenib monotherapy or in combination with conventional chemotherapy, has been evaluated in various settings in AML, including front-line, relapsed or refractory disease including post-allograft failures and, more recently, as post-transplant maintenance therapy. Encouraging data have emerged with several other agents like lestaurtinib, midostaurin, crenolanib, gilteritinib and quizartinib. Although transient responses to FLT3 inhibitors are often observed in case of disease relapse, the most promising approach is the use of FLT3 inhibitors either in combination with induction chemotherapy or as consolidation/maintenance therapy after allogeneic hematopoietic cell transplantation. In this review, we summarize the clinical data on sorafenib and other FLT3 inhibitors in AML.

  1. Positive Werkzeuge mit hohem IQ

    NASA Astrophysics Data System (ADS)

    Luik, Matthias

    Fräsen ist ein Verfahren, auf welches im modernen Produktionsprozess nicht verzichtet werden kann. Dabei stellt die zunehmende Komplexität der zu fertigenden Bauteile ganz neue Herausforderungen an ein Werkzeug. Konnten früher Bauteile nur mit hohem Aufwand durch Erodieren oder Außenräumen hergestellt werden, müssen heute bereits Fräswerkzeuge für solche Bearbeitungsaufgaben aus Zeitund Kostengründen eingesetzt werden. Dies führt dazu, dass viele Bauteile heute in einer Aufspannung bearbeitbar sind, welche früher nur durch mehrmaliges Umspannen erzeugt werden konnten. Um Bearbeitungszeiten und -kosten dabei gering zu halten, müssen aber dennoch universelle Werkzeuge eingesetzt werden, welche für verschiedenste Bearbeitungsaufgaben ausgelegt sind.

  2. Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs.

    PubMed

    Maiques-Diaz, A; Chou, F S; Wunderlich, M; Gómez-López, G; Jacinto, F V; Rodriguez-Perales, S; Larrayoz, M J; Calasanz, M J; Mulloy, J C; Cigudosa, J C; Alvarez, S

    2012-06-01

    The AML1-ETO fusion protein, which is present in 10-15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an 'inactive' chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.

  3. Targeting CD157 in AML using a novel, Fc-engineered antibody construct.

    PubMed

    Krupka, Christina; Lichtenegger, Felix S; Köhnke, Thomas; Bögeholz, Jan; Bücklein, Veit; Roiss, Michael; Altmann, Torben; Do, To Uyen; Dusek, Rachel; Wilson, Keith; Bisht, Arnima; Terrett, Jon; Aud, Dee; Pombo-Villar, Esteban; Rohlff, Christian; Hiddemann, Wolfgang; Subklewe, Marion

    2017-05-30

    Antibody-based immunotherapy represents a promising strategy to eliminate chemorefractory leukemic cells in acute myeloid leukemia (AML). In this study, we evaluated a novel Fc-engineered antibody against CD157 (MEN1112) for its suitability as immunotherapy in AML. CD157 was expressed in 97% of primary AML patient samples. A significant, albeit lower expression level of CD157 was observed within the compartment of leukemia-initiating cells, which are supposed to be the major source of relapse. In healthy donor bone marrow, CD157 was expressed on CD34+ cells. In ex vivo assays, MEN1112 triggered natural killer (NK) cell-mediated cytotoxicity against AML cell lines and primary AML cells. Compared to its parental analogue, the Fc-engineered antibody exhibited higher antibody dependent cellular cytotoxicity responses. Using NK cells from AML patients, we observed heterogeneous MEN1112-mediated cytotoxicity against AML cells, most likely due to well-documented defects in AML-NK cells and corresponding inter-patient variations in NK cell function. Cytotoxicity could not be correlated to the time after completion of chemotherapy. In summary, we could demonstrate that CD157 is strongly expressed in AML. MEN1112 is a promising antibody construct that showed high cytotoxicity against AML cells and warrants further clinical testing. Due to variability in NK-cell function of AML patients, the time of application during the course of the disease as well as combinatorial strategies might influence treatment results.

  4. Exploiting Cellular Pathways to Develop New Treatment Strategies for AML

    PubMed Central

    Fathi, Amir T.; Grant, Steven; Karp, Judith E.

    2010-01-01

    The standard approaches to the treatment of acute myeloid leukemia (AML) have been predominantly based on cytarabine and anthracyclines. Yet, the outcomes associated with AML continue to be poor, especially for those patients who are older or carry higher-risk disease. In recent years, extensive research has led to the development and study of novel agents which target AML by diverse and varied mechanisms. Among these are targeted therapeutics such as kinase inhibitors and oligonuceotide constructs. These aim to suppress the production or activity of proteins, such as FLT3 and BCL2, among others, and thus disrupt related signaling cascades essential for leukemogenesis and proliferation. In addition, other agents like flavopiridol appear to target the myeloid blast by various mechanisms including suppression of cyclin dependent kinases and interference with nucleotide synthesis. Another class of novel therapies includes inhibitors of histone deacetylase, which cause growth arrest and apoptosis through histone acetylation and resultant conformational changes. Clinical trials are now studying these and other agents alone and in combination with traditional cytotoxic therapies, with some encouraging results. In this review, we aim to provide a summary of the preclinical and clinical investigations of selected promising agents currently under study. PMID:20056334

  5. Mutation position within evolutionary subclonal architecture in AML.

    PubMed

    Welch, John S

    2014-10-01

    Cytogenetic data suggest that acute myeloid leukemia (AML) develops through a process of branching evolution, especially during relapse and progression. Recent genomic data from AML cases using digital sequencing, temporal comparisons, xenograft cloning, and single-cell analysis indicate that most, if not all, AML cases emerge through branching evolution. According to a review of the current literature, the balanced translocations (t[15;17], t[8;21], and inv[16]) and nucleotide variants in DNMT3A and TET2 most commonly occur in the founding clone at diagnosis. These mutations are rarely gained or lost at relapse, and the latter 2 mutations are observed in elderly subjects with mosaic hematopoiesis antedating overt leukemia. In contrast, +8, +13, +22, -X, -Y, and nucleotide variants in FLT3, NRAS/KRAS, WT1, and KIT frequently occur in subclones and are observed either to emerge or to be lost at relapse. Because drugs that target mutations within a subclone are unlikely to eliminate all leukemic cells, it will be essential to understand not only which mutations a patient has but also how they organize within the leukemic subclonal architecture.

  6. Unfälle mit Pkw

    NASA Astrophysics Data System (ADS)

    Burg, Heinz

    Der Verkehrsunfall ereignete sich innerorts auf einer Kreuzung mit rechts vor links Regelung. Es galt dort die allgemeine Geschwindigkeitsbegrenzung auf 50 km/h. Zur Unfallzeit war es hell und trocken. Die Fahrbahn hatte eine Schwarzdecke.

  7. Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells.

    PubMed

    Yan, F; Shen, N; Pang, J X; Zhang, Y W; Rao, E Y; Bode, A M; Al-Kali, A; Zhang, D E; Litzow, M R; Li, B; Liu, S J

    2017-06-01

    Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid-binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and interleukin (IL)-6 in the sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and signal transducer and activator of transcription factor 3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15(INK4B) tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15(INK4B) expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia.

  8. Fusion of dendritic cells and CD34+CD38- acute myeloid leukemia (AML) cells potentiates targeting AML-initiating cells by specific CTL induction.

    PubMed

    Lei, Zhang; Zhang, Gui-Mei; Hong, Mei; Feng, Zuo-Hua; Huang, Bo

    2009-05-01

    Distinct leukemia-initiating cells (L-ICs) represent a critical target for therapeutic intervention of acute myeloid leukemia (AML). A potential strategy to eradicate L-ICs is to generate L-IC-specific cytotoxic T lymphocytes (CTLs). However, owing to rarity and immortality of L-ICs, it is difficult for antigen-presenting cells to capture L-ICs for specific antigen presentation. Here, we report a novel approach by fusing allogeneic dendritic cells (DCs) and CD34CD38 AML progenitor cells, through which specific CTLs were effectively induced, leading to the cytolysis to AML-initiating cells. Fusion of either DC/CD34CD38 AML cell or DC/CD34 AML cell could effectively induce the proliferation and activation of CTLs. However, only the former CTLs could effectively attack AML progenitor cells, and result in the unkilled progenitor/initiating cells losing the abilities of active proliferation in vitro and engraftment in NOD-SCID mice. These findings suggest that AML progenitor/initiating cell-specific CTLs may be generated based on allogeneic DC/progenitor cell fusion strategy; the induced CTLs may potentially eradicate AML by targeting L-ICs directly or indirectly.

  9. Carnitine transporter CT2 (SLC22A16) is over-expressed in acute myeloid leukemia (AML) and target knockdown reduces growth and viability of AML cells.

    PubMed

    Wu, Yan; Hurren, Rose; MacLean, Neil; Gronda, Marcela; Jitkova, Yulia; Sukhai, Mahadeo A; Minden, Mark D; Schimmer, Aaron D

    2015-08-01

    AML (acute myeloid leukemia) cells have a unique reliance on mitochondrial metabolism and fatty acid oxidation (FAO). Thus, blocking FAO is a potential therapeutic strategy to target these malignant cells. In the current study, we assessed plasma membrane carnitine transporters as novel therapeutic targets for AML. We examined the expression of the known plasma membrane carnitine transporters, OCTN1, OCTN2, and CT2 in AML cell lines and primary AML samples and compared expression to normal hematopoietic cells. Of the three carnitine transporters, CT2 demonstrated the greatest differential expression between AML and normal cells. Using shRNA, we knocked down CT2 and demonstrated that target knockdown impaired the function of the transporter. In addition, knockdown of CT2 reduced the growth and viability of AML cells with high expression of CT2 (OCI-AML2 and HL60), but not low expression. CT2 knockdown reduced basal oxygen consumption without a concomitant increase in glycolysis. Thus, CT2 may be a novel target for a subset of AML.

  10. Whole genome and transcriptome analysis of a novel AML cell line with a normal karyotype.

    PubMed

    Gosse, Géraldine; Celton, Magalie; Lamontagne, Vikie; Forest, Audrey; Wilhelm, Brian T

    2015-07-01

    Acute myeloid leukemia (AML) occurs when hematopoietic progenitor cells acquire genetic defects blocking the regulation of normal growth and differentiation. Although recurrent translocations have been identified in AML, almost half of adult AML patients present with a normal karyotype (NK-AML). While cell line models exist to study AML, they frequently have abnormal/unstable karyotypes, while primary cells from NK-AML patients are difficult to maintain in vitro. Here we provide a thorough molecular characterization of a recently established cell line, CG-SH, which has normal cytogenetics, representing a useful new model for NK-AML. Using high-throughput DNA sequencing, we first defined the genetic background of this cell line. In addition to identifying potentially deleterious SNVs in genes relevant to AML, we also found insertions in both GATA2 and EZH2, two genes previously linked to AML. We further characterized the growth of this model system in vitro with a cytokine mix that promotes faster cell growth. We assessed gene expression changes after the addition of cytokines to the culture media and found differential expression in genes implicated in proliferation, apoptosis and differentiation. Our results provide a detailed molecular characterization of genetic defects in this cell line derived from an NK-AML patient.

  11. Spontaneous Remission in an Older Patient with Relapsed FLT3 ITD Mutant AML

    PubMed Central

    Mendler, Jason H.; Evans, Andrew; Deeb, George; Starostik, Petr; Wallace, Paul K.; Wang, Eunice S.

    2016-01-01

    Spontaneous remission (SR) of acute myeloid leukemia (AML) is a very rare phenomenon. AML characterized by FLT3 internal tandem duplication (FLT3 ITD) is typically associated with an aggressive clinical course with rapid progression, relapse, and short overall survival in the absence of transplantation. We report here the first case of SR of FLT3 ITD mutant AML in the literature. Our patient was an elderly woman with relapsed NPM1 and FLT3 ITD mutant AML whose disease underwent SR for a brief duration without precipitating cause. We review the potential immune mechanisms underlying SR in AML and discuss the implications for novel immunotherapeutic approaches for FLT3 mutant AML. PMID:28127477

  12. Oncogenic pathways of AML1-ETO in acute myeloid leukemia: multifaceted manipulation of marrow maturation

    PubMed Central

    Elagib, Kamaleldin E.; Goldfarb, Adam N.

    2007-01-01

    The leukemic fusion protein AML1-ETO occurs frequently in human acute myeloid leukemia (AML) and has received much attention over the past decade. An initial model for its pathogenetic effects emphasized the conversion of a hematopoietic transcriptional activator, RUNX1 (or AML1), into a leukemogenic repressor which blocked myeloid differentiation at the level of target gene regulation. This view has been absorbed into a larger picture of AML1-ETO pathogenesis, encompassing dysregulation of hematopoietic stem cell homeostasis at several mechanistic levels. Recent reports have highlighted a multifaceted capacity of AML1-ETO directly to inhibit key hematopoietic transcription factors that function as tumor suppressors at several nodal points during hematopoietic differentiation. A new model is presented in which AML1-ETO coordinates expansion of the stem cell compartment with diminished lineage commitment and with genome instability. PMID:17125917

  13. CD56 and RUNX1 isoforms in AML prognosis and their therapeutic potential.

    PubMed

    Zaidi, Syed Z A; Motabi, Ibraheem H; Al-Shanqeeti, Ali

    2016-09-01

    Neural cell adhesion molecule (NCAM/CD56) expression in acute myeloid leukemia (AML) has been associated with extramedullary leukemia, multidrug resistance, shorter remission and survival. Recently, Bloomfield et al. published a succinct review of issues surrounding the AML prognostication and current therapeutics. However, we want to reiterate the prognostic value and therapeutic potential of CD56 that is frequently expressed in AML as was also reported by their own group earlier. In addition, novel RUNX1 isoforms contribute in controlling CD56 expression in AML cells. Anti-CD56 antibody therapy deserves exploration as an arsenal against AML patients expressing CD56. Relevantly, targeting RNA splicing machinery or RUNX1 isoform-specific siRNA may also become part of future therapeutic strategies for AML with CD56 overexpression.

  14. DNMT3A mutation is a poor prognosis biomarker in AML: results of a meta-analysis of 4500 AML patients.

    PubMed

    Shivarov, Velizar; Gueorguieva, Ralitza; Stoimenov, Angel; Tiu, Ramon

    2013-11-01

    Somatic DNA methyl transferase 3A (DNMT3A) mutations have been recognized recently as recurrent molecular aberrations in acute myeloid leukemia (AML). The precise role of these mutations in leukemogenesis remains elusive but a number of studies have already been conducted to study their potential prognostic value in AML patients with variable results. We performed a meta-analysis on published data from over 4500 AML patients to provide robust evidence supporting DNMT3A mutation testing in clinical setting for AML patients. Our meta-analysis showed that DNMT3A mutations were associated with M4 and M5 AML subtypes. Those mutations conferred significantly worse prognosis with both shorter OS (p=0.0004) and shorter RFS (p=0.002). Notably, DNMT3A mutations appeared to be an independent adverse prognostic factor also in younger patients with normal cytogenetics AML (OS (p=0.01) and RFS (p=0.0005)) and also in the subgroup of patients with high risk genotypes defined according to the criteria of the European Leukemia Net (ELN) (OS (p=0.002)). Therefore, DNMT3A mutational status can improve the risk stratification of AML patients in the setting of integrated mutational profiling.

  15. ENL links histone acetylation to oncogenic gene expression in AML

    PubMed Central

    Wan, Liling; Wen, Hong; Li, Yuanyuan; Lyu, Jie; Xi, Yuanxin; Hoshii, Takayuki; Joseph, Julia; Wang, Xiaolu; Loh, Yong-Hwee E.; Erb, Michael A.; Souza, Amanda L.; Bradner, James E.; Shen, Li; Li, Wei; Li, Haitao; Allis, C. David; Armstrong, Scott A.; Shi, Xiaobing

    2017-01-01

    Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs1. Recognition of modified histones by “reader” proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of BET bromodomain inhibitors2, 3. We recently identified the YEATS domain as a novel acetyllysine-binding module4, yet its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralog AF9, is required for disease maintenance in acute myeloid leukaemia (AML). CRISPR-Cas9 mediated depletion of ENL led to anti-leukemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and ChIP-seq analyses revealed that ENL binds to acetylated histone H3, and colocalizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemias. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced RNA polymerase II recruitment to ENL target genes, leading to suppression of oncogenic gene expression programs. Importantly, disruption of ENL’s functionality further sensitized leukaemia cells to BET inhibitors. Together, our study identifies ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in AML and suggests that displacement of ENL from chromatin may be a promising epigenetic therapy alone or in combination with BET inhibitors for AML. PMID:28241141

  16. Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

    PubMed Central

    Petrov, Ivan; Suntsova, Maria; Mutorova, Olga; Sorokin, Maxim; Garazha, Andrew; Ilnitskaya, Elena; Spirin, Pavel; Larin, Sergey; Zhavoronkov, Alex; Kovalchuk, Olga; Prassolov, Vladimir; Roumiantsev, Alexander; Buzdin, Anton

    2016-01-01

    Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies. PMID:27870639

  17. Cell Type Dependent Regulation of Multidrug Resistance-1 Gene Expression by AML1-ETO

    PubMed Central

    Hines, Robert; Boyapati, Anita; Zhang, Dong-Er

    2007-01-01

    The AML1-ETO fusion protein is generated from the 8;21 chromosome translocation that is commonly identified in acute myeloid leukemia. AML1-ETO is a DNA binding transcription factor and has been demonstrated to play a critical role in promoting leukemogenesis. Therefore, it is important to define the molecular mechanism of AML1-ETO in the regulation of gene expression. Here, we report that the effect of AML1-ETO on the promoter of multidrug resistance-1 (MDR1) gene, a known AML1-ETO target, is highly cell type specific. Besides observing repression of the MDR1 promoter in C33A and CV-1 cells as reported previously, AML1-ETO strongly activated the promoter in K562 and B210 cells. More importantly, this activation required both the AML1 and ETO portions of the fusion protein, but did not depend on the AML1 binding site in MDR1 promoter. Furthermore, results from promoter deletion analysis and chromatin immunoprecipitation assays suggested that this activation effect was likely through the influence of the general transcription machinery rather than promoter-specific factors. Based on these data, we propose that AML1-ETO may have opposing effects on gene expression depending on the various conditions of the cellular environment. PMID:17590361

  18. Targeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models

    PubMed Central

    Wu, Qing; Bhole, Aaron; Qin, Haiyan; Karp, Judith; Malek, Sami; Cowell, John K; Ren, Mingqiang

    2016-01-01

    Although over expression of chimeric FGFR1 kinase consistently leads to the development of AML in the rare Stem Cell Leukemia and Lymphoma syndrome, we now show that overexpression of FGFR1 is also seen in up to 20% of non-syndromic, de novo AML. To determine whether targeting FGFR1 in both of these AML subtypes can suppress leukemogenesis, we evaluated the effects of different FGFR1 inhibitors in a side-by-side comparison for their ability to affect in vitro proliferation in FGFR1 overexpressing murine and human cells lines. Three newly developed pan-FGFR inhibitors, AZD4547, BGJ398 and JNJ42756493, show a significantly improved efficacy over the more established FGFR inhibitors, PD173074 and TKI258. To examine whether targeting FGFR1 suppresses leukemogenesis in de novo AML in vivo, we created xenografts in immunocompromized mice from primary, de novo AML that showed > 3-fold increased expression of FGFR1. Using BGJ398, the most potent inhibitor identified in the in vitro studies, AML progression in these mice was significantly suppressed compared with vehicle treated animals and overall survival improved. Importantly, no difference in disease course or survival was seen in AML xenografts that did not show overexpression of FGFR1. These observations support the idea that FGFR1 is a driver oncogene in de novo, FGFR1-overexpressing AML and that molecularly targeted therapies using FGFR1 inhibitors may provide a valuable therapeutic regimen for all FGFR1-overexpressing AML. PMID:27391347

  19. Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells.

    PubMed

    Petrov, Ivan; Suntsova, Maria; Mutorova, Olga; Sorokin, Maxim; Garazha, Andrew; Ilnitskaya, Elena; Spirin, Pavel; Larin, Sergey; Kovalchuk, Olga; Prassolov, Vladimir; Zhavoronkov, Alex; Roumiantsev, Alexander; Buzdin, Anton

    2016-11-19

    Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies.

  20. MPL expression on AML blasts predicts peripheral blood neutropenia and thrombocytopenia.

    PubMed

    Rauch, Philipp J; Ellegast, Jana M; Widmer, Corinne C; Fritsch, Kristin; Goede, Jeroen S; Valk, Peter J M; Löwenberg, Bob; Takizawa, Hitoshi; Manz, Markus G

    2016-11-03

    Although the molecular pathways that cause acute myeloid leukemia (AML) are increasingly well understood, the pathogenesis of peripheral blood cytopenia, a major cause of AML mortality, remains obscure. A prevailing assumption states that AML spatially displaces nonleukemic hematopoiesis from the bone marrow. However, examining an initial cohort of 223 AML patients, we found no correlation between bone marrow blast content and cytopenia, questioning the displacement theory. Measuring serum concentration of thrombopoietin (TPO), a key regulator of hematopoietic stem cells and megakaryocytes, revealed loss of physiologic negative correlation with platelet count in AML cases with blasts expressing MPL, the thrombopoietin (scavenging) receptor. Mechanistic studies demonstrated that MPL(hi) blasts could indeed clear TPO, likely therefore leading to insufficient cytokine levels for nonleukemic hematopoiesis. Microarray analysis in an independent multicenter study cohort of 437 AML cases validated MPL expression as a central predictor of thrombocytopenia and neutropenia in AML. Moreover, t(8;21) AML cases demonstrated the highest average MPL expression and lowest average platelet and absolute neutrophil counts among subgroups. Our work thus explains the pathophysiology of peripheral blood cytopenia in a relevant number of AML cases.

  1. The molecular signature of AML mesenchymal stromal cells reveals candidate genes related to the leukemogenic process.

    PubMed

    Binato, Renata; de Almeida Oliveira, Nathalia Correa; Du Rocher, Barbara; Abdelhay, Eliana

    2015-12-01

    Acute myeloid leukemia (AML) is a heterogeneous disease characterized by myeloid precursor proliferation in the bone marrow, apoptosis reduction and differentiation arrest. Although there are several studies in this field, events related to disease initiation and progression remain unknown. The malignant transformation of hematopoietic stem cells (HSC) is thought to generate leukemic stem cells, and this transformation could be related to changes in mesenchymal stromal cell (hMSC) signaling. Thus, the aim of this work was to analyze the gene expression profile of hMSC from AML patients (hMSC-AML) compared to healthy donors hMSCs (hMSC-HD). The results showed a common molecular signature for all hMSC-AML. Other assays were performed with a large number of patients and the results confirmed a molecular signature that is capable of distinguishing hMSC-AML from hMSC-HD. Moreover, CCL2 and BMP4 genes encode secreted proteins that could affect HSCs. To verify whether these proteins are differentially expressed in AML patients, ELISA was performed with plasma samples. CCL2 and BMP4 proteins are differentially expressed in AML patients, indicating changes in hMSC-AML signaling. Altogether, hMSCs-AML signaling alterations could be an important factor in the leukemic transformation process.

  2. SCLLTargeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models.

    PubMed

    Wu, Qing; Bhole, Aaron; Qin, Haiyan; Karp, Judith; Malek, Sami; Cowell, John K; Ren, Mingqiang

    2016-08-02

    Although over expression of chimeric FGFR1 kinase consistently leads to the development of AML in the rare Stem Cell Leukemia and Lymphoma syndrome, we now show that overexpression of FGFR1 is also seen in up to 20% of non-syndromic, de novo AML. To determine whether targeting FGFR1 in both of these AML subtypes can suppress leukemogenesis, we evaluated the effects of different FGFR1 inhibitors in a side-by-side comparison for their ability to affect in vitro proliferation in FGFR1 overexpressing murine and human cells lines. Three newly developed pan-FGFR inhibitors, AZD4547, BGJ398 and JNJ42756493, show a significantly improved efficacy over the more established FGFR inhibitors, PD173074 and TKI258. To examine whether targeting FGFR1 suppresses leukemogenesis in de novo AML in vivo, we created xenografts in immunocompromized mice from primary, de novo AML that showed > 3-fold increased expression of FGFR1. Using BGJ398, the most potent inhibitor identified in the in vitro studies, AML progression in these mice was significantly suppressed compared with vehicle treated animals and overall survival improved. Importantly, no difference in disease course or survival was seen in AML xenografts that did not show overexpression of FGFR1. These observations support the idea that FGFR1 is a driver oncogene in de novo, FGFR1-overexpressing AML and that molecularly targeted therapies using FGFR1 inhibitors may provide a valuable therapeutic regimen for all FGFR1-overexpressing AML.

  3. Minimally invasive thyroidectomy (MIT): indications and results.

    PubMed

    Docimo, Giovanni; Salvatore Tolone, Salvatore; Gili, Simona; d'Alessandro, A; Casalino, G; Brusciano, L; Ruggiero, Roberto; Docimo, Ludovico

    2013-01-01

    To establish if the indication for different approaches for thyroidectomy and the incision length provided by means of pre-operative assessment of gland volume and size of nodules resulted in safe and effective outcomes and in any notable aesthetic or quality-of-life impact on patients. Ninehundred eightytwo consecutive patients, undergoing total thyroidectomy, were enrolled. The thyroid volume and maximal nodule diameter were measured by means of ultrasounds. Based on ultrasounds findings, patients were divided into three groups: minimally invasive video assisted thyroidectomy (MIVAT), minimally invasive thyroidectomy (MIT) and conventional thyroidectomy (CT) groups. The data concerning the following parameters were collected: operative time, postoperative complications, postoperative pain and cosmetic results. The MIVAT group included 179 patients, MIT group included 592 patients and CT group included 211 patients. Incidence of complications did not differ significantly in each group. In MIVAT and MIT group, the perception of postoperative pain was less intense than CT group. The patients in the MIVAT (7±1.5) and MIT (8±2) groups were more satisfied with the cosmetic results than those in CT group (5±1.3) (p= <0.05). The MIT is a technique totally reproducible, and easily convertible to perform surgical procedures in respect of the patient, without additional complications, increased costs, and with better aesthetic results.

  4. Study of RpI22 in MDS and AML

    DTIC Science & Technology

    2016-12-01

    Notably, RPL22 inactivation is observed in10% of human T-ALL (2), where its loss correlates with poor survival. Mono-allelic inactivation or deletion of...Consistently, our collaborator found that RPL22 indeed was mutated or deleted in some MDS and AML patients. Further we found that loss of Rpl22 but not other...Rpl22-Like1 (Like1) that is induced upon Rpl22 loss . Interestingly, Rpl22 functions through the regulation of Like1. Like1 overexpression is both

  5. Assessment of Minimal Residual Disease in Standard-Risk AML.

    PubMed

    Ivey, Adam; Hills, Robert K; Simpson, Michael A; Jovanovic, Jelena V; Gilkes, Amanda; Grech, Angela; Patel, Yashma; Bhudia, Neesa; Farah, Hassan; Mason, Joanne; Wall, Kerry; Akiki, Susanna; Griffiths, Michael; Solomon, Ellen; McCaughan, Frank; Linch, David C; Gale, Rosemary E; Vyas, Paresh; Freeman, Sylvie D; Russell, Nigel; Burnett, Alan K; Grimwade, David

    2016-02-04

    Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations

  6. Transcription of the AML1/ETO chimera is guided by the P2 promoter of the AML1 gene in the Kasumi-1 cell line.

    PubMed

    Markova, Elena N; Kantidze, Omar L; Razin, Sergey V

    2012-12-01

    Chromosomal translocation t (8;21)(q22;22) is one of the most frequent cytogenetic abnormalities found in acute myeloid leukaemia (AML). It generates the AML1/ETO fusion gene, which itself supports human haematopoietic stem cell self-renewal. However, the mechanism guiding transcription of this chimeric gene remains unclear. In our work, we attempted to shed light on this essential issue. We investigated the promoter from which transcription of the AML1/ETO gene is initiated and defined the three-dimensional structure of the whole rearranged locus. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Isoform-Specific Potentiation of Stem and Progenitor Cell Engraftment by AML1/RUNX1

    PubMed Central

    Tsuzuki, Shinobu; Hong, Dengli; Gupta, Rajeev; Matsuo, Keitaro; Seto, Masao; Enver, Tariq

    2007-01-01

    Background AML1/RUNX1 is the most frequently mutated gene in leukaemia and is central to the normal biology of hematopoietic stem and progenitor cells. However, the role of different AML1 isoforms within these primitive compartments is unclear. Here we investigate whether altering relative expression of AML1 isoforms impacts the balance between cell self-renewal and differentiation in vitro and in vivo. Methods and Findings The human AML1a isoform encodes a truncated molecule with DNA-binding but no transactivation capacity. We used a retrovirus-based approach to transduce AML1a into primitive haematopoietic cells isolated from the mouse. We observed that enforced AML1a expression increased the competitive engraftment potential of murine long-term reconstituting stem cells with the proportion of AML1a-expressing cells increasing over time in both primary and secondary recipients. Furthermore, AML1a expression dramatically increased primitive and committed progenitor activity in engrafted animals as assessed by long-term culture, cobblestone formation, and colony assays. In contrast, expression of the full-length isoform AML1b abrogated engraftment potential. In vitro, AML1b promoted differentiation while AML1a promoted proliferation of progenitors capable of short-term lymphomyeloid engraftment. Consistent with these findings, the relative abundance of AML1a was highest in the primitive stem/progenitor compartment of human cord blood, and forced expression of AML1a in these cells enhanced maintenance of primitive potential both in vitro and in vivo. Conclusions These data demonstrate that the “a” isoform of AML1 has the capacity to potentiate stem and progenitor cell engraftment, both of which are required for successful clinical transplantation. This activity is consistent with its expression pattern in both normal and leukaemic cells. Manipulating the balance of AML1 isoform expression may offer novel therapeutic strategies, exploitable in the contexts of

  8. Generating Peripheral Blood Derived Lymphocytes Reacting Against Autologous Primary AML Blasts

    PubMed Central

    Mehta, Rohtesh S.; Chen, Xiaohua; Antony, Jeyaraj; Boyiadzis, Michael; Szabolcs, Paul

    2015-01-01

    Expanding on our prior studies with cord blood T-cells, we hypothesized that primary AML-reactive autologous T-cells could be generated ex vivo under immunomodulatory conditions. We purified AML and T-cells from 8 newly diagnosed high-risk patients. After 2 weeks expansion, T-cells were stimulated with IFN-γ treated autologous AML weekly X 3, IL-15 and agonistic anti-CD28 antibody. CTL and ELISpot assays tested functionality; RT-qPCR tested AML and T-cell gene expression profiles. Based on combined positive ELIspot and CTL assays, T-cells reactive against AML were generated in 5/8 patients. Treg proportion declined post-co-cultures in reactive T-cell samples. AML-reactive T-cells displayed an activated gene expression profile. “Resistant” AML blasts displayed genes associated with immunosuppressive MDSC. We discuss our approach to creating primary AML-reactive autologous T-cell and limitations that require further work. Our study provides a platform for future research targeting on generating autologous leukemia reactive T-cells. PMID:26849076

  9. IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.

    PubMed

    Schinke, Carolina; Giricz, Orsolya; Li, Weijuan; Shastri, Aditi; Gordon, Shanisha; Barreyro, Laura; Barreryo, Laura; Bhagat, Tushar; Bhattacharyya, Sanchari; Ramachandra, Nandini; Bartenstein, Matthias; Pellagatti, Andrea; Boultwood, Jacqueline; Wickrema, Amittha; Yu, Yiting; Will, Britta; Wei, Sheng; Steidl, Ulrich; Verma, Amit

    2015-05-14

    Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML.

  10. Spontaneous remission in three cases of AML M5 with NPM1 mutation

    PubMed Central

    Camus, Vincent; Etancelin, Pascaline; Jardin, Fabrice; Lenain, Pascal; Contentin, Nathalie; Daliphard, Sylvie; Buchonnet, Gérard; Lemasle, Emilie; Lanic, Hélène; Leprêtre, Stéphane; Penther, Dominique; Dubois, Sydney; Tilly, Hervé; Bastard, Christian; Stamatoullas, Aspasia

    2015-01-01

    Key Clinical Message Patients with NPM1-mutated AML M5 who develop spontaneous remission (SR) after antibiotic therapy at diagnosis seem to form a favorable prognosis and chemo sensitive subtype. We report three cases of AML M5 patients with the same genotype that experienced transient SR and are now leukemia free after standard treatment. PMID:26576281

  11. Transcriptomic and proteomic analysis of mouse radiation-induced acute myeloid leukaemia (AML)

    PubMed Central

    Badie, Christophe; Blachowicz, Agnieszka; Barjaktarovic, Zarko; Finnon, Rosemary; Michaux, Arlette; Sarioglu, Hakan; Brown, Natalie; Manning, Grainne; Benotmane, M. Abderrafi; Tapio, Soile; Polanska, Joanna; Bouffler, Simon D.

    2016-01-01

    A combined transcriptome and proteome analysis of mouse radiation-induced AMLs using two primary AMLs, cell lines from these primaries, another cell line and its in vivo passage is reported. Compared to haematopoietic progenitor and stem cells (HPSC), over 5000 transcriptome alterations were identified, 2600 present in all materials. 55 and 3 alterations were detected in the proteomes of the cell lines and primary/in vivo passage material respectively, with one common to all materials. In cell lines, approximately 50% of the transcriptome changes are related to adaptation to cell culture, and in the proteome this proportion was higher. An AML ‘signature’ of 17 genes/proteins commonly deregulated in primary AMLs and cell lines compared to HPSCs was identified and validated using human AML transcriptome data. This also distinguishes primary AMLs from cell lines and includes proteins such as Coronin 1, pontin/RUVBL1 and Myeloperoxidase commonly implicated in human AML. C-Myc was identified as having a key role in radiation leukaemogenesis. These data identify novel candidates relevant to mouse radiation AML pathogenesis, and confirm that pathways of leukaemogenesis in the mouse and human share substantial commonality. PMID:27250028

  12. Spontaneous remission in three cases of AML M5 with NPM1 mutation.

    PubMed

    Camus, Vincent; Etancelin, Pascaline; Jardin, Fabrice; Lenain, Pascal; Contentin, Nathalie; Daliphard, Sylvie; Buchonnet, Gérard; Lemasle, Emilie; Lanic, Hélène; Leprêtre, Stéphane; Penther, Dominique; Dubois, Sydney; Tilly, Hervé; Bastard, Christian; Stamatoullas, Aspasia

    2015-11-01

    Patients with NPM1-mutated AML M5 who develop spontaneous remission (SR) after antibiotic therapy at diagnosis seem to form a favorable prognosis and chemo sensitive subtype. We report three cases of AML M5 patients with the same genotype that experienced transient SR and are now leukemia free after standard treatment.

  13. Mutation Patterns of 16 Genes in Primary and Secondary Acute Myeloid Leukemia (AML) with Normal Cytogenetics

    PubMed Central

    Fernandez-Mercado, Marta; Yip, Bon Ham; Pellagatti, Andrea; Davies, Carwyn; Larrayoz, María José; Kondo, Toshinori; Pérez, Cristina; Killick, Sally; McDonald, Emma-Jane; Odero, María Dolores; Agirre, Xabier; Prósper, Felipe; Calasanz, María José; Wainscoat, James S.; Boultwood, Jacqueline

    2012-01-01

    Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML. PMID:22912701

  14. Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML.

    PubMed

    Botezatu, Lacramioara; Michel, Lars C; Helness, Anne; Vadnais, Charles; Makishima, Hideki; Hönes, Judith M; Robert, François; Vassen, Lothar; Thivakaran, Aniththa; Al-Matary, Yahya; Lams, Robert F; Schütte, Judith; Giebel, Bernd; Görgens, André; Heuser, Michael; Medyouf, Hind; Maciejewski, Jaroslaw; Dührsen, Ulrich; Möröy, Tarik; Khandanpour, Cyrus

    2016-08-01

    Epigenetic changes can contribute to development of acute myeloid leukemia (AML), a malignant disease of the bone marrow. A single-nucleotide polymorphism of transcription factor growth factor independence 1 (GFI1) generates a protein with an asparagine at position 36 (GFI1(36N)) instead of a serine at position 36 (GFI1(36S)), which is associated with de novo AML in humans. However, how GFI1(36N) predisposes to AML is poorly understood. To explore the mechanism, we used knock-in mouse strains expressing GFI1(36N) or GFI1(36S). Presence of GFI1(36N) shortened the latency and increased the incidence of AML in different murine models of myelodysplastic syndrome/AML. On a molecular level, GFI1(36N) induced genomewide epigenetic changes, leading to expression of AML-associated genes. On a therapeutic level, use of histone acetyltransferase inhibitors specifically impeded growth of GFI1(36N)-expressing human and murine AML cells in vitro and in vivo. These results establish, as a proof of principle, how epigenetic changes in GFI1(36N)-induced AML can be targeted.

  15. Generating Peripheral Blood Derived Lymphocytes Reacting Against Autologous Primary AML Blasts.

    PubMed

    Mehta, Rohtesh S; Chen, Xiaohua; Antony, Jeyaraj; Boyiadzis, Michael; Szabolcs, Paul

    2016-01-01

    Expanding on our prior studies with cord blood T cells, we hypothesized that primary acute myeloid leukemia (AML)-reactive autologous T cells could be generated ex vivo under immunomodulatory conditions. We purified AML and T cells from 8 newly diagnosed high-risk patients. After 2 weeks expansion, T cells were stimulated with interferon-γ-treated autologous AML weekly × 3, interleukin-15, and agonistic anti-CD28 antibody. Cytotoxic T cells and ELISpot assays tested functionality; reverse transcriptase quantitative polymerase chain reaction tested AML and T-cell gene expression profiles. On the basis of combined positive ELIspot and cytotoxic T cells assays, T cells reactive against AML were generated in 5 of 8 patients. Treg proportion declined after cocultures in reactive T-cell samples. AML-reactive T cells displayed an activated gene expression profile. "Resistant" AML blasts displayed genes associated with immunosuppressive myeloid-derived suppressor cells. We discuss our approach to creating primary AML-reactive autologous T cell and limitations that require further work. Our study provides a platform for future research targeting on generating autologous leukemia-reactive T cells.

  16. GFI1 as a novel prognostic and therapeutic factor for AML/MDS.

    PubMed

    Hönes, J M; Botezatu, L; Helness, A; Vadnais, C; Vassen, L; Robert, F; Hergenhan, S M; Thivakaran, A; Schütte, J; Al-Matary, Y S; Lams, R F; Fraszscak, J; Makishima, H; Radivoyevitch, T; Przychodzen, B; da Conceição Castro, S V; Görgens, A; Giebel, B; Klein-Hitpass, L; Lennartz, K; Heuser, M; Thiede, C; Ehninger, G; Dührsen, U; Maciejewski, J P; Möröy, T; Khandanpour, C

    2016-06-01

    Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.

  17. MCM7 polymorphisms associated with the AML relapse and overall survival.

    PubMed

    Lee, Jin Sol; Cheong, Hyun Sub; Koh, Youngil; Ahn, Kwang-Sung; Shin, Hyoung Doo; Yoon, Sung-Soo

    2017-01-01

    The minichromosome maintenance complex component 7 (MCM7) encodes a member of MCM complex, which plays a critical role in the initiation of gene replication. Due to the importance of MCM complex, MCM7 gene has been regarded as a candidate gene for cancer development. In the present study, seven MCM7 polymorphisms were genotyped in 344 subjects composed of 103 acute myeloid leukemia (AML) patients and 241 normal controls to examine the possible associations between MCM7 polymorphisms and the risk of AML. MCM7 polymorphisms were not associated with the risk of AML (P > 0.05). However, MCM7 polymorphisms were significantly related to the relapse of AML and overall survival. The rs2070215 (N144S) showed a protective effect to the risk of AML relapse (OR = 0.37; P (corr) = 0.02). In haplotype analyses, the ht1 and ht2 showed significant associations with the risk of AML relapse (P (corr) = 0.02-0.03). In addition, rs1534309 showed an association with the overall survival of AML patients. Patients with major homozygote genotype (CC) of rs1534309 showed a higher survival rate than the patients with other genotypes (CG and GG). The results of the present study indicate that MCM7 polymorphisms may be able to predict the prognosis of AML patients.

  18. Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts.

    PubMed

    Le Dieu, Rifca; Taussig, David C; Ramsay, Alan G; Mitter, Richard; Miraki-Moud, Faridah; Fatah, Rewas; Lee, Abigail M; Lister, T Andrew; Gribben, John G

    2009-10-29

    Understanding how the immune system in patients with cancer interacts with malignant cells is critical for the development of successful immunotherapeutic strategies. We studied peripheral blood from newly diagnosed patients with acute myeloid leukemia (AML) to assess the impact of this disease on the patients' T cells. The absolute number of peripheral blood T cells is increased in AML compared with healthy controls. An increase in the absolute number of CD3+56+ cells was also noted. Gene expression profiling on T cells from AML patients compared with healthy donors demonstrated global differences in transcription suggesting aberrant T-cell activation patterns. These gene expression changes differ from those observed in chronic lymphocytic leukemia (CLL), indicating the heterogeneous means by which different tumors evade the host immune response. However, in common with CLL, differentially regulated genes involved in actin cytoskeletal formation were identified, and therefore the ability of T cells from AML patients to form immunologic synapses was assessed. Although AML T cells could form conjugates with autologous blasts, their ability to form immune synapses and recruit phosphotyrosine signaling molecules to the synapse was significantly impaired. These findings identify T-cell dysfunction in AML that may contribute to the failure of a host immune response against leukemic blasts.

  19. Incentives in IT Yield Success at MIT.

    ERIC Educational Resources Information Center

    Hanson, Mary

    2001-01-01

    Describes the role of information technology (IT) at the Massachusetts Institute of Technology, explaining that attention to the unique characteristics of an MIT education and incentives for sustainable change are central to its IT efforts. Discusses various IT initiatives, such as Project Athena, provision on campus, international efforts, and…

  20. Wrestling with Pedagogical Change: The TEAL Initiative at MIT

    ERIC Educational Resources Information Center

    Breslow, Lori

    2010-01-01

    In the late 1990s, the physics department at the Massachusetts Institute of Technology (MIT) had a problem. The department was responsible for teaching the two required physics courses that are part of the General Institute Requirements (GIRs), MIT's core curriculum--Physics I (mechanics, or in MIT parlance, 8.01) and Physics II (electricity and…

  1. AML1-ETO inhibits maturation of multiple lymphohematopoietic lineages and induces myeloblast transformation in synergy with ICSBP deficiency.

    PubMed

    Schwieger, Maike; Löhler, Jürgen; Friel, Jutta; Scheller, Marina; Horak, Ivan; Stocking, Carol

    2002-11-04

    The translocation (8;21), generating the AML1-ETO fusion protein, is one of the most frequent chromosomal abnormalities associated with acute myelogenous leukemia (AML). To elucidate its role in oncogenesis, bone marrow (BM) cells were infected with a retroviral vector carrying AML1-ETO and transplanted into mice. In contrast to previous transgenic mouse models, we show that AML1-ETO directly stimulates granulopoiesis, suppresses erythropoiesis, and impairs the maturation of myeloid, B, and T lymphoid cells in vivo. To determine the significance of earlier findings that expression of the tumor suppressor ICSBP is often downregulated in AML myeloblasts, AML1-ETO was introduced into BM cells derived from mice lacking the interferon regulatory factor ICSBP. Our findings demonstrate that AML1-ETO synergizes with an ICSBP deficiency to induce myeloblastic transformation in the BM, reminiscent of AML.

  2. AML1-ETO Inhibits Maturation of Multiple Lymphohematopoietic Lineages and Induces Myeloblast Transformation in Synergy with ICSBP Deficiency

    PubMed Central

    Schwieger, Maike; Löhler, Jürgen; Friel, Jutta; Scheller, Marina; Horak, Ivan; Stocking, Carol

    2002-01-01

    The translocation (8;21), generating the AML1-ETO fusion protein, is one of the most frequent chromosomal abnormalities associated with acute myelogenous leukemia (AML). To elucidate its role in oncogenesis, bone marrow (BM) cells were infected with a retroviral vector carrying AML1-ETO and transplanted into mice. In contrast to previous transgenic mouse models, we show that AML1-ETO directly stimulates granulopoiesis, suppresses erythropoiesis, and impairs the maturation of myeloid, B, and T lymphoid cells in vivo. To determine the significance of earlier findings that expression of the tumor suppressor ICSBP is often downregulated in AML myeloblasts, AML1-ETO was introduced into BM cells derived from mice lacking the interferon regulatory factor ICSBP. Our findings demonstrate that AML1-ETO synergizes with an ICSBP deficiency to induce myeloblastic transformation in the BM, reminiscent of AML. PMID:12417632

  3. [Dendritic cells (DC) induced from acute myeloid leukemia (AML) cells with cytokine cocktails].

    PubMed

    Yan, Kuang-hua; You, Sheng-guo; Bian, Shou-geng; Ma, Guan-jie; Ge, Wei; Ma, Shuang; Liu, Shi-he; Zhao, Chun-hua

    2003-07-01

    To explore the feasibility of DC being in vitro induced from AML cells with cytokine cocktails and their biological properties. AML cells were cultured in either presence or absence of cytokine cocktails. DC were studied for morphology, and cytochemical and immunofluorescent staining. Functions of DC were examined by MLC, FITC-conjugated dextran uptake test, and LDH release assay. RT-PCR and FISH were used to analyze the specific fusion genes of culture-derived DC. Classical DC morphological changes occurred in all 15 cultured AML cells. DC-associated surface molecules such as CD(1a), CD(80), CD(86), CD(106), CD(83) and HLA-DR were upregulated (P < 0.05). The allostimulatory abilities of culture-derived DC were significantly higher than those of AML cells uncultured or cultured in the absence of cytokines (P < 0.05). Culture-derived DC only in the presence of GM-CSF + IL-4 have phagocytotic activities. CTL assay was performed in 5 of the 15 samples. At effector/target ratio of 20:1, auto-T lymphocytes primed with the culture-derived DC exhibited no more killing activity to auto-AML cells than those stimulated by IL-2 or uncultured AML cells. Culture-derived DC presenced the native AML-specific aberrant karyotype and related fusion gene. Cytokine cocktails could in vitro induce AML cells into DC with classical morphology, immunophenotype and function. DC maturity induced by different cytokine cocktails could be variable. Culture-derived DC were originated from the native AML cells. AML cells could make the auto-T lymphocyte anergy.

  4. Cytidine deaminase polymorphisms and worse treatment response in normal karyotype AML.

    PubMed

    Hyo Kim, Lyoung; Sub Cheong, Hyun; Koh, Youngil; Ahn, Kwang-Sung; Lee, Chansu; Kim, Hyung-Lae; Doo Shin, Hyoung; Yoon, Sung-Soo

    2015-12-01

    The cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of the cytarabine (AraC) into a 1-β-D-arabinofuranosyluracil (AraU), an inactive metabolite that plays a crucial role in lowering the amount of AraC, a key chemotherapeutic drug, in the treatment of patients with acute myeloid leukemia (AML). In this study, we hypothesized that CDA polymorphisms were associated with the AraC metabolism for AML treatment and/or related clinical phenotypes. We analyzed 16 polymorphisms of CDA among 50 normal karyotype AML (NK-AML) patients, 45 abnormal karyotype AML (AK-AML) patients and 241 normal controls (NC). Several polymorphisms and haplotypes, rs532545, rs2072671, rs471760, rs4655226, rs818194 and CDA-ht3, were found to have a strong correlation with NK-AML compared with NC and these polymorphisms also revealed strong linkage disequilibrium with each other. Among them, rs2072671 (79A>C), which is located in a coding region and the resultant amino acid change K27Q, showed significant associations with NK-AML compared with NC (P=0.009 and odds ratio=2.44 in the dominant model). The AC and CC genotypes of rs2072671 (79A>C) were significantly correlated with shorter overall survival rates (P=0.03, hazard ratio=1.84) and first complete remission duration (P=0.007, hazard ratio=3.24) compared with the AA genotype in the NK-AML patients. Our results indicate that rs2072671 in CDA may be an important prognostic marker in NK-AML patients.

  5. [Initial subretinal localization of acute myeloblastic leukemia (AML5) recurrence].

    PubMed

    Le Gall, S; François, S; Urier, N; Genevieve, F; d'Hermies, F; Rachieru, P; Ifrah, N

    2001-10-13

    Reduced visual acuity in patients with acute leucemia can result from many causes including an ocular localization. A patient previously treated for acute myeloblastic leucemia-5 (AML5) developed bilateral vision impairment related to a subretinal localization of the leucemia. Meningeal and bone marrow relapse followed. The subretinal localization responded only to massive systemic steroid treatment. Although asymptomatic, ocular localizations are frequent in leucemia. Their prognostic impact depends on the ocular structure involved and on the chronology of onset--early or late in the leucemia course. The underlying pathophysiological mechanism of ocular involvement remains unexplained but hyperleucocytosis at presentation may be a risk factor and would justify at least systematic specialized examinations and discussion of prophylactic treatment.

  6. STAT activation status differentiates leukemogenic from non-leukemogenic stem cells in AML and is suppressed by arsenic in t(6;9)-positive AML.

    PubMed

    Oancea, Claudia; Rüster, Brigitte; Brill, Boris; Roos, Jessica; Heinssmann, Maria; Bug, Gesine; Mian, Afsar Ali; Guillen, Nathalie Andrea; Kornblau, Steven M; Henschler, Reinhard; Ruthardt, Martin

    2014-11-01

    Acute myeloid leukemia (AML) is characterized by an aberrant self-renewal of hematopoietic stem cells (HSC) and a block in differentiation. The major therapeutic challenge is the characterization of the leukemic stem cell as a target for the eradication of the disease. Until now the biology of AML-associated fusion proteins (AAFPs), such as the t(15;17)-PML/RARα, t(8;21)-RUNX1/RUNX1T1 and t(6;9)-DEK/NUP214, all able to induce AML in mice, was investigated in different models and genetic backgrounds, not directly comparable to each other. To avoid the bias of different techniques and models we expressed these three AML-inducing oncogenes in an identical genetic background and compared their influence on the HSC compartment in vitro and in vivo. These AAFPs exerted differential effects on HSCs and PML/RARα, similar to DEK/NUP214, induced a leukemic phenotype from a small subpopulation of HSCs with a surface marker pattern of long-term HSC and characterized by activated STAT3 and 5. In contrast the established AML occurred from mature populations in the bone marrow. The activation of STAT5 by PML/RARα and DEK/NUP214 was confirmed in t(15;17)(PML/RARα) and t(6;9)(DEK/NUP214)-positive patients as compared to normal CD34+ cells. The activation of STAT5 was reduced upon the exposure to Arsenic which was accompanied by apoptosis in both PML/RARα- and DEK/NUP214-positive leukemic cells. These findings indicate that in AML the activation of STATs plays a decisive role in the biology of the leukemic stem cell. Furthermore we establish exposure to arsenic as a novel concept for the treatment of this high risk t(6;9)-positive AML.

  7. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML

    PubMed Central

    Wong, Terrence N.; Miller, Christopher A.; Klco, Jeffery M.; Petti, Allegra; Demeter, Ryan; Helton, Nichole M.; Li, Tiandao; Fulton, Robert S.; Heath, Sharon E.; Mardis, Elaine R.; Westervelt, Peter; DiPersio, John F.; Walter, Matthew J.; Welch, John S.; Graubert, Timothy A.; Wilson, Richard K.; Ley, Timothy J.

    2016-01-01

    There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient’s nonleukemic hematopoietic population. Here, we report that 5 of 15 patients with genetic clearance of their founding AML clone after induction chemotherapy had a concomitant expansion of a hematopoietic population unrelated to the initial AML. These populations frequently harbored somatic mutations in genes recurrently mutated in AML or myelodysplastic syndromes and were detectable at very low frequencies at the time of AML diagnosis. These results suggest that nonleukemic hematopoietic stem and progenitor cells, harboring specific aging-acquired mutations, may have a competitive fitness advantage after induction chemotherapy, expand, and persist long after the completion of chemotherapy. Although the clinical importance of these “rising” clones remains to be determined, it will be important to distinguish them from leukemia-related populations when assessing for molecular responses to induction chemotherapy. PMID:26631115

  8. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML.

    PubMed

    Wong, Terrence N; Miller, Christopher A; Klco, Jeffery M; Petti, Allegra; Demeter, Ryan; Helton, Nichole M; Li, Tiandao; Fulton, Robert S; Heath, Sharon E; Mardis, Elaine R; Westervelt, Peter; DiPersio, John F; Walter, Matthew J; Welch, John S; Graubert, Timothy A; Wilson, Richard K; Ley, Timothy J; Link, Daniel C

    2016-02-18

    There is interest in using leukemia-gene panels and next-generation sequencing to assess acute myelogenous leukemia (AML) response to induction chemotherapy. Studies have shown that patients with AML in morphologic remission may continue to have clonal hematopoiesis with populations closely related to the founding AML clone and that this confers an increased risk of relapse. However, it remains unknown how induction chemotherapy influences the clonal evolution of a patient's nonleukemic hematopoietic population. Here, we report that 5 of 15 patients with genetic clearance of their founding AML clone after induction chemotherapy had a concomitant expansion of a hematopoietic population unrelated to the initial AML. These populations frequently harbored somatic mutations in genes recurrently mutated in AML or myelodysplastic syndromes and were detectable at very low frequencies at the time of AML diagnosis. These results suggest that nonleukemic hematopoietic stem and progenitor cells, harboring specific aging-acquired mutations, may have a competitive fitness advantage after induction chemotherapy, expand, and persist long after the completion of chemotherapy. Although the clinical importance of these "rising" clones remains to be determined, it will be important to distinguish them from leukemia-related populations when assessing for molecular responses to induction chemotherapy.

  9. Epigenetic landscape of the TERT promoter: a potential biomarker for high risk AML/MDS.

    PubMed

    Zhao, Xin; Tian, Xin; Kajigaya, Sachiko; Cantilena, Caroline R; Strickland, Stephen; Savani, Bipin N; Mohan, Sanjay; Feng, Xingmin; Keyvanfar, Keyvan; Dunavin, Neil; Townsley, Danielle M; Dumitriu, Bogdan; Battiwalla, Minoo; Rezvani, Katayoun; Young, Neal S; Barrett, A John; Ito, Sawa

    2016-11-01

    Although recent observations implicate the importance of telomerase activity in acute myeloid leukaemia (AML), the roles of epigenetic regulations of the TERT gene in leukaemogenesis, drug resistance and clinical prognosis in AML are not fully understood. We developed a quantitative pyrosequencing-based methylation assay covering the TERT proximal promoter and a partial exon 1 (TERTpro/Ex1) region and tested both cell lines and primary leukaemia cells derived from AML and AML with preceding myelodysplastic syndrome (AML/MDS) patients (n = 43). Prognostic impact of methylation status of the upstream TERT promoter region was assessed by the Kaplan-Meier method. The activity of the telomerase inhibitor, imetelstat, was measured using leukaemia cell lines. The TERTpro/Ex1 region was highly methylated in all cell lines and primary leukaemia cells showed diverse methylation profiles. Most cases showed hypermethylated regions at the upstream TERTpro/Ex1 region, which were associated with inferior patient survival. TERTpro/Ex1 methylation status was correlated with the cytotoxicity to imetelstat and its combination with hypomethylating agent enhanced the cytotoxicity of imetelstat. AML cell lines and primary blasts harbour distinct TERTpro/Ex1 methylation profiles that could serve as a prognostic biomarker of AML. However, validation in a large cohort of patients is necessary to confirm our findings.

  10. Targeting PDK1 with dichloroacetophenone to inhibit acute myeloid leukemia (AML) cell growth.

    PubMed

    Qin, Lijun; Tian, Yun; Yu, Zhenlong; Shi, Dingbo; Wang, Jingshu; Zhang, Changlin; Peng, Ruoyu; Chen, Xuezhen; Liu, Congcong; Chen, Yiming; Huang, Wenlin; Deng, Wuguo

    2016-01-12

    Pyruvate dehydrogenase kinase-1 (PDK1), a key metabolic enzyme involved in aerobic glycolysis, is highly expressed in many solid tumors. Small molecule compound DAP (2,2-dichloroacetophenone) is a potent inhibitor of PDK1. Whether targeting PDK1 with DAP can inhibit acute myeloid leukemia (AML) and how it works remains unknown. In this study, we evaluated the effect of inhibition of PDK1 with DAP on cell growth, apoptosis and survival in AML cells and identified the underlying mechanisms. We found that treatment with DAP significantly inhibited cell proliferation, increased apoptosis induction and suppressed autophagy in AML cells in vitro, and inhibited tumor growth in an AML mouse model in vivo. We also showed that inhibition of PDK1 with DAP increased the cleavage of pro-apoptotic proteins (PARP and Caspase 3) and decreased the expression of the anti-apoptotic proteins (BCL-xL and BCL-2) and autophagy regulators (ULK1, Beclin-1 and Atg). In addition, we found that DAP inhibited the PI3K/Akt signaling pathway. Furthermore, we demonstrated that PDK1 interacted with ULK1, BCL-xL and E3 ligase CBL-b in AML cells, and DPA treatment could inhibit the interactions. Collectively, our results indicated that targeting PDK1 with DAP inhibited AML cell growth via multiple signaling pathways and suggest that targeting PDK1 may be a promising therapeutic strategy for AMLs.

  11. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes.

    PubMed

    Matre, Polina; Velez, Juliana; Jacamo, Rodrigo; Qi, Yuan; Su, Xiaoping; Cai, Tianyu; Chan, Steven M; Lodi, Alessia; Sweeney, Shannon R; Ma, Helen; Davis, Richard Eric; Baran, Natalia; Haferlach, Torsten; Su, Xiaohua; Flores, Elsa Renee; Gonzalez, Doriann; Konoplev, Sergej; Samudio, Ismael; DiNardo, Courtney; Majeti, Ravi; Schimmer, Aaron D; Li, Weiqun; Wang, Taotao; Tiziani, Stefano; Konopleva, Marina

    2016-11-29

    Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes.

  12. Repression of GSK3 restores NK cell cytotoxicity in AML patients.

    PubMed

    Parameswaran, Reshmi; Ramakrishnan, Parameswaran; Moreton, Stephen A; Xia, Zhiqiang; Hou, Yongchun; Lee, Dean A; Gupta, Kalpana; deLima, Marcos; Beck, Rose C; Wald, David N

    2016-04-04

    Natural killer cells from acute myeloid leukaemia patients (AML-NK) show a dramatic impairment in cytotoxic activity. The exact reasons for this dysfunction are not fully understood. Here we show that the glycogen synthase kinase beta (GSK3β) expression is elevated in AML-NK cells. Interestingly, GSK3 overexpression in normal NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK3 inactivation enhances their cytotoxic activity. Mechanistic studies reveal that the increased cytotoxic activity correlates with an increase in AML-NK cell conjugates. GSK3 inhibition promotes the conjugate formation by upregulating LFA expression on NK cells and by inducing ICAM-1 expression on AML cells. The latter is mediated by increased NF-κB activation in response to TNF-α production by NK cells. Finally, GSK3-inhibited NK cells show significant efficacy in human AML mouse models. Overall, our work provides mechanistic insights into the AML-NK dysfunction and a potential NK cell therapy strategy.

  13. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes

    PubMed Central

    Jacamo, Rodrigo; Qi, Yuan; Su, Xiaoping; Cai, Tianyu; Chan, Steven M.; Lodi, Alessia; Sweeney, Shannon R.; Ma, Helen; Davis, Richard Eric; Baran, Natalia; Haferlach, Torsten; Su, Xiaohua; Flores, Elsa Renee; Gonzalez, Doriann; Konoplev, Sergej; Samudio, Ismael; DiNardo, Courtney; Majeti, Ravi; Schimmer, Aaron D.; Li, Weiqun; Wang, Taotao; Tiziani, Stefano; Konopleva, Marina

    2016-01-01

    Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes. PMID:27806325

  14. Sorafenib inhibition of Mcl-1 accelerates ATRA induced apoptosis in differentiation responsive AML cells

    PubMed Central

    Wang, Rui; Xia, Lijuan; Gabrilove, Janice; Waxman, Samuel; Jing, Yongkui

    2015-01-01

    Purpose All trans retinoic acid (ATRA) is successful in treating acute promyelocytic leukemia (APL) by inducing terminal differentiation-mediated cell death, but it has limited activity in non-APL acute myeloid leukemia (AML). We aim to improve ATRA therapy of AML by enhancing apoptosis through repression of the anti-apoptotic proteins Bcl-2 and Mcl-1. Experimental Design APL and AML cell lines, as well as primary AML samples, were used to explore the mechanisms regulating differentiation and apoptosis during ATRA treatment. Stable transfection and gene silencing with siRNA were used to identify the key factors that inhibit apoptosis during induction of differentiation and drugs that accelerate apoptosis. Results In differentiation responsive AML cells, ATRA treatment induces long-lasting repression of Bcl-2 while first up-modulating and then reducing the Mcl-1 level. The Mcl-1 level appears to serve as a gatekeeper between differentiation and apoptosis. During differentiation induction, activation of MEK/ERK and PI3K/Akt pathways by ATRA leads to activation of p90RSK and inactivation of glycogen synthase kinase 3β (GSK3β), which increase Mcl-1 levels by increasing its translation and stability. Sorafenib blocks ATRA-induced Mcl-1 increase by reversing p90RSK activation and GSK3β inactivation, maintains the repressed Bcl-2 level, and enhances ATRA induced apoptosis in non-APL AML cell lines and in primary AML cells. Conclusion Inhibition of Mcl-1 is required for apoptosis induction in ATRA differentiation responsive AML cells. ATRA and Sorafenib can be developed as a novel drug combination therapy for AML patients because this drug combination augments apoptosis by inhibiting Bcl-2 and Mcl-1. PMID:26459180

  15. Flight research with the MIT Daedalus prototype

    NASA Technical Reports Server (NTRS)

    Bussolari, Steven R.; Youngren, Harold H.; Langford, John S.

    1987-01-01

    The MIT Light Eagle human-powered aircraft underwent long-duration testing over Rogers Dry Lake in California during January, 1987. Designed as a prototype for the MIT Daedalus Project, the Light Eagle's forty-eight flights provided pilot training, established new distance records for human-powered flight, and provided quantitative data through a series of instrumented flight experiments. The experiments focused on: (1) evaluating physiological loads on the pilot, (2) determining airframe power requirements, and (3) developing an electronic flight control system. This paper discusses the flight test program, its results and their implications for the follow-on Daedalus aircraft, and the potential uses of the Light Eagle as a low Reynolds number testbed.

  16. Abdichtungen im Verbund mit Fliesen und Platten

    NASA Astrophysics Data System (ADS)

    Platts, Thomas

    Abdichtungen im Verbund mit Fliesen und Platten, im Folgenden auch als Verbundabdichtungen oder mit Kurzzeichen als AIV bezeichnet, haben sich in der Baupraxis insbesondere in Innenräumen wegen des vereinfachten konstruktiven Aufbaus gegenüber Bahnenabdichtungen nach DIN 18195-5 [14.1] in der Mehrzahl der Ausführungen durchgesetzt und bewährt. Sie können im Innen- und Außenbereich angeordnet werden und sind dadurch gekennzeichnet, dass die Nutzschicht in Boden- und Wandbereichen im Dünnbettverfahren unmittelbar auf die Abdichtung aufgebracht wird. Aufwändige Zwischenschichten oder Einbauteile wie armierter Putz, Telleranker etc. entfallen (Bild 14.1) und es lassen sich geringere Aufbauhöhen realisieren.

  17. Grundlegende Steuerungsverfahren im heterogenen Logistiknetz mit Kanban

    NASA Astrophysics Data System (ADS)

    Dickmann, Eva; Dickmann, Philipp; Lödding, Hermann; Möller, Niklas; Rücker, Thomas; Schneider, Herfried M.; Zäh, Michael F.

    In vielen Unternehmen werden heterogene (verschiedene) Steuerungen in einem abgestimmten Konzept kombiniert. Je nach Anwendungsfall und Rahmenbedingungen werden Kombinationen allgemein bekannter Steuerungen oder Steuerungsvarianten gemischt eingesetzt, um eine optimale Steuerung für unterschiedliche Fälle zu erreichen. Hierbei stehen neben den bekannten und weit verbreiteten Methoden, wie Material Requirements Planning (MRP) oder Kanban, auch weniger bekannte oder neue Methoden zur Auswahl, wie die Produktionssteuerung mit dezentraler, bestandsorientierter Fertigungsregelung (DBF). Kanban ist ein simples und effizientes Steuerungskonzept, das in der klassischen Form für spezifische einfache Anwendungsfälle umsetzbar ist. Hochentwickelte Steuerungsalgorithmen können helfen, komplexe Abläufe optimal abzubilden. Mit einer grundlegenden Vereinfachung der Abläufe kann allerdings in vielen Fällen ein wesentlich stärkerer und umfassender Verbesserungseffekt erzielt werden. Die wesentliche Fragestellung sollte folglich lauten: Warum ist der Ablauf nicht mit einer einfachen Steuerung wie Kanban abzubilden? Um die Vorteile des Konzepts auch in untypischen Bereichen anwenden zu können, sind jedoch verschiedene Varianten oder Kanban-ähnliche Steuerungsmethoden entstanden. Darüber hinaus sind in der Praxis hybride Steuerungen im Einsatz, welche so kombiniert werden, dass die Zusammensetzung anspruchsvolle Eigenschaftsbilder noch exakt abbildet. In der Praxis basieren die Steuerungsentscheidungen nur zu einem kleinen Teil auf den eigentlichen Steuerungsalgorithmen, wie sie uns das MRP-System zur Verfügung stellt. Moderne Steuerungswelten" schließen alle relevanten Informationsquellen in eine heterogene Entscheidungsmatrix mit ein. Letztlich zählt nicht, ob die Entscheidung auf den Informationen aus dem MRP-System oder auf Softfacts basierend getroffen wurde, sondern nur, ob die Entscheidung erfolgreich war.

  18. The NPM1 Mutation Type Has No Impact on Survival in Cytogenetically Normal AML

    PubMed Central

    Pastore, Friederike; Greif, Philipp A.; Schneider, Stephanie; Ksienzyk, Bianka; Mellert, Gudrun; Zellmeier, Evelyn; Braess, Jan; Sauerland, Cristina M.; Heinecke, Achim; Krug, Utz; Berdel, Wolfgang E.; Buechner, Thomas; Woermann, Bernhard; Hiddemann, Wolfgang; Spiekermann, Karsten

    2014-01-01

    NPM1 mutations represent frequent genetic alterations in patients with acute myeloid leukemia (AML) associated with a favorable prognosis. Different types of NPM1 mutations have been described. The purpose of our study was to evaluate the relevance of different NPM1 mutation types with regard to clinical outcome. Our analyses were based on 349 NPM1-mutated AML patients treated in the AMLCG99 trial. Complete remission rates, overall survival and relapse-free survival were not significantly different between patients with NPM1 type A or rare type mutations. The NPM1 mutation type does not seem to play a role in risk stratification of cytogenetically normal AML. PMID:25299584

  19. Mishap Investigation Team (MIT) - Barksdale AFB, Louisiana

    NASA Technical Reports Server (NTRS)

    Stepaniak, Philip

    2005-01-01

    The Shuttle Program is organized to support a Shuttle mishap using the resources of the MIT. The afternoon of Feb. 1, 2003, the MIT deployed to Barksdale AFB. This location became the investigative center and interim storage location for crewmembers received from the Lufkin Disaster Field Office (DFO). Working under the leadership of the MIT Lead, the medical team executed a short-term plan that included search, recovery, and identification including coordination with the Armed Forces Institute of Pathology Temporary operations was set up at Barksdale Air Force Base for two weeks. During this time, coordination with the DFO field recovery teams, AFIP personnel, and the crew surgeons was on going. In addition, the crewmember families and NASA management were updated daily. The medical team also dealt with public reports and questions concerning biological and chemical hazards, which were coordinated with SPACEHAB, Inc., Kennedy Space Center (KSC) Medical Operations and the Johnson Space Center (JSC) Space Medicine office. After operations at Barksdale were concluded the medical team transitioned back to Houston and a long-term search, recovery and identification plan was developed.

  20. MIT validation probe acceptance test procedure

    SciTech Connect

    Escamilla, S.A.

    1994-08-23

    As part of the Multi-Functional Instrument Trees (MITs) a Validation Probe is being fabricated by Los Alamos National Laboratories (LANL). The Validation Probe assembly is equipped with a Winch, depth counter, and a Resistance Temperature Detector (RTD) which will render a means for verifying the temperature readings of which will render a means for verifying the temperature readings of the MIT thermocouples. The purpose of this Acceptance Test Procedure (ATP) is to provide verification that the Validation Probe functions properly and accordingly to LANL design and specification. This ATP will be used for all Validation Probes procured from LANL. The ATP consists of a receiving inspection, RTD ambient temperature; RTD electrical failure, RTD insulation resistance, and accurate depth counter operation inspections. The Validation Probe is composed of an intank probe, a cable and winching system, and a riser extension (probe guide) which bolts onto the MIT. The validation`s thermal sensor is an RTD that is housed in a 0.062 inch diameter, magnesium oxide fill, 316 stainless steel tube. The sheath configuration provides a means for spring loading the sensor firmly against the validation tube`s inner wall. A 45 pound cylindrical body is connected above the sheath and is used as a force to lower the probe into the tank. This cylindrical body also provides the means to interconnect both electrically and mechanically to the winch system which lowers the probe to a specified location within the validation tube located in the tank.

  1. Mishap Investigation Team (MIT) - Barksdale AFB, Louisiana

    NASA Technical Reports Server (NTRS)

    Stepaniak, Philip

    2005-01-01

    The Shuttle Program is organized to support a Shuttle mishap using the resources of the MIT. The afternoon of Feb. 1, 2003, the MIT deployed to Barksdale AFB. This location became the investigative center and interim storage location for crewmembers received from the Lufkin Disaster Field Office (DFO). Working under the leadership of the MIT Lead, the medical team executed a short-term plan that included search, recovery, and identification including coordination with the Armed Forces Institute of Pathology Temporary operations was set up at Barksdale Air Force Base for two weeks. During this time, coordination with the DFO field recovery teams, AFIP personnel, and the crew surgeons was on going. In addition, the crewmember families and NASA management were updated daily. The medical team also dealt with public reports and questions concerning biological and chemical hazards, which were coordinated with SPACEHAB, Inc., Kennedy Space Center (KSC) Medical Operations and the Johnson Space Center (JSC) Space Medicine office. After operations at Barksdale were concluded the medical team transitioned back to Houston and a long-term search, recovery and identification plan was developed.

  2. Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia.

    PubMed

    Zhou, Bin; Li, Haiying; Xing, Chongyun; Ye, Haige; Feng, Jianhua; Wu, Jianbo; Lu, Zhongqiu; Fang, Jing; Gao, Shenmeng

    2017-03-15

    AML1-ETO is the most common oncoprotein leading to acute myeloid leukemia (AML), in which 5-year survival rate is only about 30%. However, currently there are no specific therapies for AML patients with AML1-ETO. Here, we report that AML1-ETO protein is rapidly degraded by Honokiol (HNK), a natural phenolic compound isolated from the plant Magnolia officinalis. HNK induced the degradation of AML1-ETO in a concentration- and time-dependent manner in leukemic cell lines and primary AML blasts with t(8;21) translocation. Mechanistically, HNK obviously increased the expression of UbcH8, an E2-conjugase for the degradation of AML1-ETO, through triggering accumulation of acetylated histones in the promoter region of UbcH8. Knockdown of UbcH8 by small hairpin RNAs (shRNAs) prevented HNK-induced degradation of AML-ETO, suggesting that UbcH8 plays a critical role in the degradation of AML1-ETO. HNK inhibited cell proliferation and induced apoptotic death without activation of caspase-3, which was reported to cleave and degrade AML1-ETO protein. Thus, HNK-induced degradation of AML1-ETO is independent of activation of caspase-3. Finally, HNK reduced the angiogenesis and migration in Kasumi-1-injected zebrafish, decreased xenograft tumor size in a xenograft leukemia mouse model, and prolonged the survival time in mouse C1498 AML model. Collectively, HNK might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. The leukemogenic t(8;21) fusion protein AML1-ETO controls ribosomal RNA genes and associates with nucleolar organizing regions at mitotic chromosomes

    PubMed Central

    Bakshi, Rachit; Zaidi, Sayyed K.; Pande, Sandhya; Hassan, Mohammad Q.; Young, Daniel W.; Lian, Jane B.; van Wijnen, Andre J.; Stein, Janet L.; Stein, Gary S.

    2010-01-01

    SUMMARY RUNX1/AML1 is required for definitive hematopoiesis and is frequently targeted by chromosomal translocation in acute myeloid leukemias (AML). The t(8;21) related AML1-ETO fusion protein blocks differentiation of myeloid progenitors. Here, we show by immunofluorescence microscopy that during interphase, endogenous AML1-ETO localizes to nuclear microenvironments distinct from those containing native RUNX1/AML1 protein. At mitosis, we clearly detect binding of AML1-ETO to nucleolar organizing regions (NORs) in AML derived Kasumi-1 cells and binding of RUNX1/AML1 to NORs in Jurkat cells. Both RUNX1/AML1 and AML1-ETO occupy ribosomal DNA repeats during interphase, as well as interact with the endogenous RNA Pol I transcription factor UBF-1. Promoter cytosine methylation analysis indicates that RUNX1/AML1 binds to rDNA repeats that are more highly CpG methylated than those bound by AML1-ETO. Down-regulation by RNA interference reveals that RUNX1/AML1 negatively regulates rDNA transcription, while AML1-ETO is a positive regulator in Kasumi-1 cells. Taken together, our findings identify a novel role for the leukemia-related AML1-ETO protein in epigenetic control of cell growth through upregulation of RNA Pol I-mediated ribosomal gene transcription, consistent with the hyper-proliferative phenotype of myeloid cells in AML patients. PMID:19001502

  4. MicroRNA–mRNA Pairs Associated with Outcome in AML: From In Vitro Cell-Based Studies to AML Patients

    PubMed Central

    Bhise, Neha S.; Chauhan, Lata; Shin, Miyoung; Cao, Xueyuan; Pounds, Stanley; Lamba, Vishal; Lamba, Jatinder K.

    2016-01-01

    Cytarabine is the primary chemotherapeutic agent used for treatment of acute myeloid leukemia (AML). Disease relapse after initial remission remains one of the most pressing therapeutic challenges in the treatment of AML. Relapsed disease is often resistant to cytarabine and subsequent salvage therapy is ineffective. Recent studies have shown that some microRNAs (miRNAs) are associated with prognosis, but have not yet explored the role of miRNAs in cellular response to cytarabine. We identified 20 miRNAs that associate with the in vitro cytarabine chemo-sensitivity or apoptotic response of eight AML cell lines. Out of the 20 miRNAs, data on 18 miRNAs was available in AML patients from The Cancer Genome Atlas database. Our stepwise-integrated analyses (step 1 – miRNA–target mRNA that were significantly correlated in AML patients; step 2 – mRNAs from step 1 with significant association with overall survival (OS)) identified 23 unique miRNA–mRNA pairs predictive of OS in AML patients. As expected HOX genes (HOXA9, HOXB7, and HOXA10) were identified to be regulated by miRs as well as predictive of worse OS. Additionally, miR107-Myb, miR-378-granzyme B involved in granzyme signaling and miR10a-MAP4K4 were identified to be predictive of outcome through integrated analysis. Although additional functional validations to establish clinical/pharmacologic importance of miRNA–mRNA pairs are needed, our results from RNA electrophoretic mobility shift assay confirmed binding of miR-10a, miR-378, and miR-107 with their target genes GALNT1, GZMB, and MYB, respectively. Integration of pathogenic and pharmacologically significant miRNAs and miRNA–mRNA relationships identified in our study opens up opportunities for development of targeted/miRNA-directed therapies. PMID:26858643

  5. MicroRNA-mRNA Pairs Associated with Outcome in AML: From In Vitro Cell-Based Studies to AML Patients.

    PubMed

    Bhise, Neha S; Chauhan, Lata; Shin, Miyoung; Cao, Xueyuan; Pounds, Stanley; Lamba, Vishal; Lamba, Jatinder K

    2015-01-01

    Cytarabine is the primary chemotherapeutic agent used for treatment of acute myeloid leukemia (AML). Disease relapse after initial remission remains one of the most pressing therapeutic challenges in the treatment of AML. Relapsed disease is often resistant to cytarabine and subsequent salvage therapy is ineffective. Recent studies have shown that some microRNAs (miRNAs) are associated with prognosis, but have not yet explored the role of miRNAs in cellular response to cytarabine. We identified 20 miRNAs that associate with the in vitro cytarabine chemo-sensitivity or apoptotic response of eight AML cell lines. Out of the 20 miRNAs, data on 18 miRNAs was available in AML patients from The Cancer Genome Atlas database. Our stepwise-integrated analyses (step 1 - miRNA-target mRNA that were significantly correlated in AML patients; step 2 - mRNAs from step 1 with significant association with overall survival (OS)) identified 23 unique miRNA-mRNA pairs predictive of OS in AML patients. As expected HOX genes (HOXA9, HOXB7, and HOXA10) were identified to be regulated by miRs as well as predictive of worse OS. Additionally, miR107-Myb, miR-378-granzyme B involved in granzyme signaling and miR10a-MAP4K4 were identified to be predictive of outcome through integrated analysis. Although additional functional validations to establish clinical/pharmacologic importance of miRNA-mRNA pairs are needed, our results from RNA electrophoretic mobility shift assay confirmed binding of miR-10a, miR-378, and miR-107 with their target genes GALNT1, GZMB, and MYB, respectively. Integration of pathogenic and pharmacologically significant miRNAs and miRNA-mRNA relationships identified in our study opens up opportunities for development of targeted/miRNA-directed therapies.

  6. SAB--a promising new treatment to improve remission rates in AML in the elderly?

    PubMed

    Wheatley, Keith

    2002-08-01

    This short report presents the results of a comparison of complete remission rates and reasons for failure, between two series of patients aged 60 years or over with acute myeloid leukaemia (AML), and discusses their interpretation.

  7. Timothy Ley, M.D., Advocates for Personalized Medicine in AML - TCGA

    Cancer.gov

    Oncologist Dr. Timothy Ley talks about how repurposing of existing drugs based on better understanding of the genetic basis of acute myeloid leukemia (AML) can help patients receive personalized care.

  8. Tailored strategy for AML patients receiving allogeneic peripheral blood stem cell transplantation.

    PubMed

    Sohn, Sang Kyun; Kim, Jong Gwang; Kim, Dong Hwan

    2006-10-01

    Considering the heterogeneity of acute myelogenous leukemia (AML), along with the pros and cons of allogeneic peripheral blood stem cell transplantation (PBSCT), a tailored strategy is needed to minimize the transplant-related mortality and maximize the transplant outcomes in AML patients exhibiting certain factors that have an impact on the post-transplant quality of life and outcomes. The factors that need to be considered when tailoring a strategy in an allogeneic PBSCT setting include the recipient's performance status and co-morbid disease include AML risk stratification, disease status, expected severity of graft-versus-host disease, and the necessity of a graft-versus-leukemia effect. Accordingly, this review article describes a possible tailoring strategy for AML patients receiving allogeneic PBSCT based on certain factors influencing the transplant outcome.

  9. TEL/AML-1 fusion gene. its frequency and prognostic significance in childhood acute lymphoblastic leukemia.

    PubMed

    Jamil, A; Theil, K S; Kahwash, S; Ruymann, F B; Klopfenstein, K J

    2000-10-15

    TEL gene rearrangement due to the 12;21 chromosome translocation is believed to be the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL). A study was conducted to investigate the frequency and prognostic significance of TEL/AML-1 fusion gene resulting from a cryptic t(12;21)(p13;q22). Bone marrow samples from 86 patients diagnosed over the past 5 years at Columbus Children's Hospital were analyzed by fluorescence in situ hybridization (FISH) technique for TEL/AML-1 fusion gene, using LSI((R)) DNA probes. The positive cases were analyzed for clinical outcome. Patients in this study received treatment according to Children's Cancer Group (CCG) protocols. Fifteen of the 86 cases (17%) were positive for the fusion gene. All were B-cell lineage and except for one, all were CD10 positive. TEL/AML-1 was not found in any T-cell ALL. The mean overall survival (OS) following diagnosis for the TEL/AML-1-positive group was significantly longer than for the TEL/AML-1-negative group by log-rank = 7.84, P = 0.005. Similarly, the event-free survival (EFS) after remission for the positive group (median 94.5 months) was longer than the negative group (median 57 months) by log-rank = 7.19, P = 0.007. This study confirms that the TEL/AML-1 fusion gene may be the most common genetic event in childhood ALL, occurring in 17% of the patients. It appears restricted to the B-cell lineage. In this study, the presence of a TEL/AML-1 fusion gene was statistically significant in predicting both OS and EFS, indicating a favorable clinical outcome for these patients. Screening for TEL/AML-1 should become routine at diagnosis and a useful biological variable for risk stratification in future clinical trials.

  10. Focal Adhesion Kinase as a Potential Target in AML and MDS.

    PubMed

    Carter, Bing Z; Mak, Po Yee; Wang, Xiangmeng; Yang, Hui; Garcia-Manero, Guillermo; Mak, Duncan; Mu, Hong; Ruvolo, Vivian; Qiu, Yihua; Coombes, Kevin; Zhang, Nianxiang; Ragon, Brittany; Weaver, David T; Pachter, Jonathan A; Kornblau, Steven; Andreeff, Michael

    2017-03-07

    Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell self-renewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P = 2 x 10-4) and relapse (P = 0.02) in AML. FAK expression was significantly lower in patients with FLT3-ITD (P = 0.0024) or RAS (P = 0.05) mutations and strongly correlated with p-SRC and integrinβ3 levels. FAK protein levels were significantly higher in CD34+ (P = 5.42 x 10-20) and CD34+ CD38- MDS (P = 7.62 x 10-9) cells compared to normal CD34+ cells. MDS patients with higher FAK in CD34+ cells tended to have better OS (P = 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with not transformed to AML and in AML patients who transformed from MDS compared with those with de novo AML. Co-culture with mesenchymal stromal cells (MSCs) increased FAK expression in AML cells. Inhibition of FAK decreased MSC-mediated adhesion/migration and viability of AML cells and prolonged survival in an AML xenograft murine model. Our results suggest that FAK regulates leukemia-stromal interactions and supports leukemia cell survival; hence FAK is a potential therapeutic target in myeloid leukemia.

  11. Profiling of microRNAs in AML cells following overexpression or silencing of the VEGF gene

    PubMed Central

    Li, Li; Zhu, Lixia; Wang, Yungui; Zhou, De; Zhu, Jingjing; Xie, Wanzhuo; Ye, Xiujin

    2017-01-01

    Acute myeloid leukemia (AML) is a disease of the hematopoietic progenitor cells associated with heterogeneous clonal proliferation. Vascular endothelial growth factor (VEGF) and its receptors play important roles in the regulation of angiogenesis during physiological and pathological processes. It is thought that AML cells have an autocrine VEGF pathway that contributes to the development and progression of AML. In addition, growing evidence has suggested that numerous microRNAs are involved in AML. The present study aimed to investigate the relationship between VEGF dysregulation and microRNA profiles in AML cells and patients. VEGF-overexpressing and VEGF-knockdown leukemia cells were constructed and changes in the patterns of microRNA expression were analyzed using a microRNA array. Subsequently, mononuclear cells from the blood of patients with AML showing high or low expression levels of VEGF were obtained and were used to assess the patterns of microRNA expression by reverse transcription-quantitative polymerase chain reaction. The results of the present study suggested that downregulation of VEGF markedly altered the profile of microRNAs in AML cells, while upregulation of VEGF did not. Examination of clinical samples from patients with AML showed that several microRNAs were closely associated with the expression level of VEGF, including miR-20a, miR-93, miR-16-5p, miR-17-5p, miR-124-5p and miR-17-3p. These results suggested that VEGF may be a pivotal protein that can both receive and initiate signals in leukemia cells. PMID:28123529

  12. Profiling of microRNAs in AML cells following overexpression or silencing of the VEGF gene.

    PubMed

    Li, Li; Zhu, Lixia; Wang, Yungui; Zhou, De; Zhu, Jingjing; Xie, Wanzhuo; Ye, Xiujin

    2017-01-01

    Acute myeloid leukemia (AML) is a disease of the hematopoietic progenitor cells associated with heterogeneous clonal proliferation. Vascular endothelial growth factor (VEGF) and its receptors play important roles in the regulation of angiogenesis during physiological and pathological processes. It is thought that AML cells have an autocrine VEGF pathway that contributes to the development and progression of AML. In addition, growing evidence has suggested that numerous microRNAs are involved in AML. The present study aimed to investigate the relationship between VEGF dysregulation and microRNA profiles in AML cells and patients. VEGF-overexpressing and VEGF-knockdown leukemia cells were constructed and changes in the patterns of microRNA expression were analyzed using a microRNA array. Subsequently, mononuclear cells from the blood of patients with AML showing high or low expression levels of VEGF were obtained and were used to assess the patterns of microRNA expression by reverse transcription-quantitative polymerase chain reaction. The results of the present study suggested that downregulation of VEGF markedly altered the profile of microRNAs in AML cells, while upregulation of VEGF did not. Examination of clinical samples from patients with AML showed that several microRNAs were closely associated with the expression level of VEGF, including miR-20a, miR-93, miR-16-5p, miR-17-5p, miR-124-5p and miR-17-3p. These results suggested that VEGF may be a pivotal protein that can both receive and initiate signals in leukemia cells.

  13. Biological Characteristics of the Leukemia-Associated Transcriptional Factor AML1 Disclosed by Hematopoietic Rescue of AML1-Deficient Embryonic Stem Cells by Using a Knock-in Strategy

    PubMed Central

    Okuda, Tsukasa; Takeda, Kiyoshi; Fujita, Yasuko; Nishimura, Motohiro; Yagyu, Shigeki; Yoshida, Makie; Akira, Shizuo; Downing, James R.; Abe, Tatsuo

    2000-01-01

    AML1 is one of the most frequently mutated genes associated with human acute leukemia and encodes the DNA-binding subunit of the heterodimering transcriptional factor complex, core-binding factor (CBF) (or polyoma enhancer binding protein 2 [PEBP2]). A null mutation in either AML1 or its dimerizing partner, CBFβ, results in embryonic lethality secondary to a complete block in fetal liver hematopoiesis, indicating an essential role of this transcription complex in the development of definitive hematopoiesis. The hematopoietic phenotype that results from the loss of AML1 can be replicated in vitro with a two-step culture system of murine embryonic stem (ES) cells. Using this experimental system, we now demonstrate that this hematopoietic defect can be rescued by expressing the PEBP2αB1 (AML1b) isoform under the endogenous AML1-regulatory sequences through a knock-in (targeted insertion) approach. Moreover, we demonstrate that the rescued AML1−/− ES cell clones contribute to lymphohematopoiesis within the context of chimeric animals. Rescue requires the transcription activation domain of AML1 but does not require the C-terminal VWRPY motif, which is conserved in all AML1 family members and has been shown to interact with the transcriptional corepressor, Groucho/transducin-like Enhancer of split. Taken together, these data provide compelling evidence that the phenotype seen in AML1-deficient mice is due solely to the loss of transcriptionally active AML1. PMID:10594034

  14. MIT-Skywalker: On the use of a markerless system.

    PubMed

    Goncalves, Rogerio S; Hamilton, Taya; Krebs, Hermano I

    2017-07-01

    This paper describes our efforts to employ the Microsoft Kinect as a low cost vision control system for the MIT-Skywalker, a robotic gait rehabilitation device. The Kinect enables an alternative markerless solution to control the MIT-Skywalker and allows a more user-friendly set-up. A study involving eight healthy subjects and two stroke survivors using the MIT-Skywalker device demonstrates the advantages and challenges of this new proposed approach.

  15. Myeloid maturation block by AML1-MTG16 is associated with Csf1r epigenetic downregulation.

    PubMed

    Rossetti, Stefano; Van Unen, Leontine; Touw, Ivo P; Hoogeveen, André T; Sacchi, Nicoletta

    2005-08-11

    De novo epigenetic changes at histone and DNA level that affect gene transcription in cancer may be less random than we originally thought. Leukemia fusion proteins associated with specific chromosome translocations could mechanistically determine the epigenetic fate of specific target genes critical for normal hematopoiesis. This seems to be the case with AML1-MTG16, a fusion protein resulting from the t(16;21) translocation, a hallmark of therapy-related leukemia and myelodysplastic syndrome. Here we show that AML1-MTG16 blocks both myeloid differentiation and proliferation in the 32D/WT1-mouse myeloid cell line. These biological effects can be traced to the AML1 and MTG16 moieties of the fusion protein, respectively. Further, we show that AML1-MTG16 can induce epigenetic repressive changes at the histone and DNA level of the AML1 target gene Csf1r (c-fms), encoding the macrophage colony stimulating factor receptor. We observed that, concomitant with Csf1r downregulation, 32D/WT1 cells lost the ability to undergo myeloid differentiation in response to the granulocyte macrophage colony-stimulating factor (GM-CSF). Thus, there seems to be an association between AML1-MTG16-induced myeloid maturation block and epigenetic changes of a myeloid master gene.

  16. CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression.

    PubMed

    Spencer, David H; Russler-Germain, David A; Ketkar, Shamika; Helton, Nichole M; Lamprecht, Tamara L; Fulton, Robert S; Fronick, Catrina C; O'Laughlin, Michelle; Heath, Sharon E; Shinawi, Marwan; Westervelt, Peter; Payton, Jacqueline E; Wartman, Lukas D; Welch, John S; Wilson, Richard K; Walter, Matthew J; Link, Daniel C; DiPersio, John F; Ley, Timothy J

    2017-02-23

    DNMT3A mutations occur in ∼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3A(R882H), has dominant negative activity that reduces DNA methylation activity by ∼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3A(R882) mutations. Non-leukemic hematopoietic cells with DNMT3A(R882H) displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3A(R882) mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3A(R882), while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. DEK oncogene expression during normal hematopoiesis and in Acute Myeloid Leukemia (AML).

    PubMed

    Logan, Gemma E; Mor-Vaknin, Nirit; Braunschweig, Till; Jost, Edgar; Schmidt, Pia Verena; Markovitz, David M; Mills, Ken I; Kappes, Ferdinand; Percy, Melanie J

    2015-01-01

    DEK is important in regulating cellular processes including proliferation, differentiation and maintenance of stem cell phenotype. The translocation t(6;9) in Acute Myeloid Leukemia (AML), which fuses DEK with NUP214, confers a poor prognosis and a higher risk of relapse. The over-expression of DEK in AML has been reported, but different studies have shown diminished levels in pediatric and promyelocytic leukemias. This study has characterized DEK expression, in silico, using a large multi-center cohort of leukemic and normal control cases. Overall, DEK was under-expressed in AML compared to normal bone marrow (NBM). Studying specific subtypes of AML confirmed either no significant change or a significant reduction in DEK expression compared to NBM. Importantly, the similarity of DEK expression between AML and NBM was confirmed using immunohistochemistry analysis of tissue mircorarrays. In addition, stratification of AML patients based on median DEK expression levels indicated that DEK showed no effect on the overall survival of patients. DEK expression during normal hematopoiesis did reveal a relationship with specific cell types implicating a distinct function during myeloid differentiation. Whilst DEK may play a potential role in hematopoiesis, it remains to be established whether it is important for leukemagenesis, except when involved in the t(6;9) translocation. Copyright © 2014. Published by Elsevier Inc.

  18. Evaluation of DNMT3A genetic polymorphisms as outcome predictors in AML patients

    PubMed Central

    Yuan, Xiao-Qing; Zhang, Dao-Yu; Yan, Han; Yang, Yong-Long; Zhu, Ke-Wei; Chen, Yan-Hong; Li, Xi; Yin, Ji-Ye; Li, Xiao-Lin; Zeng, Hui; Chen, Xiao-Ping

    2016-01-01

    DNMT3A mutation is known as a recurrent event in acute myelogenous leukemia (AML) patients. However, association between DNMT3A genetic polymorphisms and AML patients' outcomes is unknown. DNMT3A 11 SNPs (rs11695471, rs2289195, rs734693, rs2276598, rs1465825, rs7590760, rs13401241, rs7581217, rs749131, rs41284843 and rs7560488) were genotyped in 344 diagnostic non-FAB-M3 AML patients from southern China. Patients underwent combined chemotherapy with cytarabine and anthracyclines. DNMT3A mRNA expression was analyzed in PBMCs from randomly selected AML patients. Multivariate analysis and combined genotype analysis showed that rs2276598 was associated with increased while rs11695471 and rs734693 were associated with decreased chemosensitivity (P<0.05), while rs11695471 (worse for OS), rs2289195 (favorable for OS and DFS) and rs2276598 (favorable for DFS) were significantly associated with disease prognosis (P<0.05). In conclusion, DNMT3A polymorphisms may be potential predictive markers for AML patients' outcomes, which might improve prognostic stratification of AML. PMID:27528035

  19. Acid ceramidase is upregulated in AML and represents a novel therapeutic target

    PubMed Central

    Tan, Su-Fern; Liu, Xin; Fox, Todd E.; Barth, Brian M.; Sharma, Arati; Turner, Stephen D.; Awwad, Andy; Dewey, Alden; Doi, Kenichiro; Spitzer, Barbara; Shah, Mithun Vinod; Morad, Samy A.F.; Desai, Dhimant; Amin, Shantu; Zhu, Junjia; Liao, Jason; Yun, Jong; Kester, Mark; Claxton, David F.; Wang, Hong-Gang; Cabot, Myles C.; Schuchman, Edward H.; Levine, Ross L.; Feith, David J.; Loughran, Thomas P.

    2016-01-01

    There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML. PMID:27825124

  20. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors

    PubMed Central

    Levanon, Ditsa; Goldstein, Robert E.; Bernstein, Yael; Tang, Hua; Goldenberg, Dalia; Stifani, Stefano; Paroush, Ze’ev; Groner, Yoram

    1998-01-01

    The mammalian AML/CBFα runt domain (RD) transcription factors regulate hematopoiesis and osteoblast differentiation. Like their Drosophila counterparts, most mammalian RD proteins terminate in a common pentapeptide, VWRPY, which serves to recruit the corepressor Groucho (Gro). Using a yeast two-hybrid assay, in vitro association and pull-down experiments, we demonstrate that Gro and its mammalian homolog TLE1 specifically interact with AML1 and AML2. In addition to the VWRPY motif, other C-terminal sequences are required for these interactions with Gro/TLE1. TLE1 inhibits AML1-dependent transactivation of the T cell receptor (TCR) enhancers α and β, which contain functional AML binding sites, in transfected Jurkat T cells. LEF-1 is an additional transcription factor that mediates transactivation of TCR enhancers. LEF-1 and its Drosophila homolog Pangolin (Pan) are involved in the Wnt/Wg signaling pathway through interactions with the coactivator β-catenin and its highly conserved fly homolog Armadillo (Arm). We show that TLE/Gro interacts with LEF-1 and Pan, and inhibits LEF-1:β-catenin-dependent transcription. These data indicate that, in addition to their activity as transcriptional activators, AML1 and LEF-1 can act, through recruitment of the corepressor TLE1, as transcriptional repressors in TCR regulation and Wnt/Wg signaling. PMID:9751710

  1. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML

    PubMed Central

    Jiang, Ying; Dunbar, Andrew; Gondek, Lukasz P.; Mohan, Sanjay; Rataul, Manjot; O'Keefe, Christine; Sekeres, Mikkael

    2009-01-01

    Myelodysplastic syndromes (MDSs) are clonal hematologic disorders that frequently represent an intermediate disease stage before progression to acute myeloid leukemia (AML). As such, study of MDS/AML can provide insight into the mechanisms of neoplastic evolution. In 184 patients with MDS and AML, DNA methylation microarray and high-density single nucleotide polymorphism array (SNP-A) karyotyping were used to assess the relative contributions of aberrant DNA methylation and chromosomal deletions to tumor-suppressor gene (TSG) silencing during disease progression. Aberrant methylation was seen in every sample, on average affecting 91 of 1505 CpG loci in early MDS and 179 of 1505 loci after blast transformation (refractory anemia with excess blasts [RAEB]/AML). In contrast, chromosome aberrations were seen in 79% of early MDS samples and 90% of RAEB/AML samples, and were not as widely distributed over the genome. Analysis of the most frequently aberrantly methylated genes identified FZD9 as a candidate TSG on chromosome 7. In patients with chromosome deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome. These results indicate that aberrant methylation can cooperate with chromosome deletions to silence TSG. However, the ubiquity, extent, and correlation with disease progression suggest that aberrant DNA methylation is the dominant mechanism for TSG silencing and clonal variation in MDS evolution to AML. PMID:18832655

  2. Evaluation of DNMT3A genetic polymorphisms as outcome predictors in AML patients.

    PubMed

    Yuan, Xiao-Qing; Zhang, Dao-Yu; Yan, Han; Yang, Yong-Long; Zhu, Ke-Wei; Chen, Yan-Hong; Li, Xi; Yin, Ji-Ye; Li, Xiao-Lin; Zeng, Hui; Chen, Xiao-Ping

    2016-09-13

    DNMT3A mutation is known as a recurrent event in acute myelogenous leukemia (AML) patients. However, association between DNMT3A genetic polymorphisms and AML patients' outcomes is unknown. DNMT3A 11 SNPs (rs11695471, rs2289195, rs734693, rs2276598, rs1465825, rs7590760, rs13401241, rs7581217, rs749131, rs41284843 and rs7560488) were genotyped in 344 diagnostic non-FAB-M3 AML patients from southern China. Patients underwent combined chemotherapy with cytarabine and anthracyclines. DNMT3A mRNA expression was analyzed in PBMCs from randomly selected AML patients. Multivariate analysis and combined genotype analysis showed that rs2276598 was associated with increased while rs11695471 and rs734693 were associated with decreased chemosensitivity (P<0.05), while rs11695471 (worse for OS), rs2289195 (favorable for OS and DFS) and rs2276598 (favorable for DFS) were significantly associated with disease prognosis (P<0.05). In conclusion, DNMT3A polymorphisms may be potential predictive markers for AML patients' outcomes, which might improve prognostic stratification of AML.

  3. Human AML-iPSCs Reacquire Leukemic Properties after Differentiation and Model Clonal Variation of Disease.

    PubMed

    Chao, Mark P; Gentles, Andrew J; Chatterjee, Susmita; Lan, Feng; Reinisch, Andreas; Corces, M Ryan; Xavy, Seethu; Shen, Jinfeng; Haag, Daniel; Chanda, Soham; Sinha, Rahul; Morganti, Rachel M; Nishimura, Toshinobu; Ameen, Mohamed; Wu, Haodi; Wernig, Marius; Wu, Joseph C; Majeti, Ravindra

    2017-03-02

    Understanding the relative contributions of genetic and epigenetic abnormalities to acute myeloid leukemia (AML) should assist integrated design of targeted therapies. In this study, we generated induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements and found that they retained leukemic mutations but reset leukemic DNA methylation/gene expression patterns. AML-iPSCs lacked leukemic potential, but when differentiated into hematopoietic cells, they reacquired the ability to give rise to leukemia in vivo and reestablished leukemic DNA methylation/gene expression patterns, including an aberrant MLL signature. Epigenetic reprogramming was therefore not sufficient to eliminate leukemic behavior. This approach also allowed us to study the properties of distinct AML subclones, including differential drug susceptibilities of KRAS mutant and wild-type cells, and predict relapse based on increased cytarabine resistance of a KRAS wild-type subclone. Overall, our findings illustrate the value of AML-iPSCs for investigating the mechanistic basis and clonal properties of human AML.

  4. Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy.

    PubMed

    Gyurkocza, B; Lazarus, H M; Giralt, S

    2017-02-27

    Patients with acute myeloid leukemia (AML) who fail to achieve complete remission (CR) have a dismal prognosis. Although data suggest that durable remissions can be achieved in approximately 30% of patients with refractory or relapsed AML after allogeneic hematopoietic cell transplantation (HCT), only a small fraction of those patients are offered this therapeutic option. Importantly, patients with primary refractory AML have distinctly better outcomes following allogeneic HCT than those with refractory relapse. Access to suitable donors could be one of the main barriers in these situations. However, with recent developments in the field of allogeneic HCT, such as alternative donor sources, high-resolution HLA-typing, reduced intensity conditioning regimens and improvements in supportive care, this approach has the potential to offer long-term survival for patients with refractory and relapsed AML and should be considered as early after diagnosis as possible. Incorporating novel agents into the conditioning regimen or as post-transplant maintenance therapy could further improve outcomes and render older or medically infirm patients with refractory or relapsed AML eligible for allogeneic HCT. In this review, we summarize existing data on allogeneic HCT in patients with refractory or relapsed AML and explore novel approaches with the potential to improve outcomes in this patient population.Bone Marrow Transplantation advance online publication, 27 February 2017; doi:10.1038/bmt.2017.8.

  5. The efficacy of the ribonucleotide reductase inhibitor Didox in preclinical models of AML.

    PubMed

    Cook, Guerry J; Caudell, David L; Elford, Howard L; Pardee, Timothy S

    2014-01-01

    Acute Myeloid Leukemia (AML) is an aggressive malignancy which leads to marrow failure, and ultimately death. There is a desperate need for new therapeutics for these patients. Ribonucleotide reductase (RR) is the rate limiting enzyme in DNA synthesis. Didox (3,4-Dihydroxybenzohydroxamic acid) is a novel RR inhibitor noted to be more potent than hydroxyurea. In this report we detail the activity and toxicity of Didox in preclinical models of AML. RR was present in all AML cell lines and primary patient samples tested. Didox was active against all human and murine AML lines tested with IC50 values in the low micromolar range (mean IC50 37 µM [range 25.89-52.70 µM]). It was active against primary patient samples at concentrations that did not affect normal hematopoietic stem cells (HSCs). Didox exposure resulted in DNA damage and p53 induction culminating in apoptosis. In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit. Didox was well tolerated, as marrow from treated animals was morphologically indistinguishable from controls. Didox exposure at levels that impaired leukemia growth did not inhibit normal HSC engraftment. In summary, Didox was well tolerated and effective against preclinical models of AML.

  6. The Efficacy of the Ribonucleotide Reductase Inhibitor Didox in Preclinical Models of AML

    PubMed Central

    Cook, Guerry J.; Caudell, David L.; Elford, Howard L.; Pardee, Timothy S.

    2014-01-01

    Acute Myeloid Leukemia (AML) is an aggressive malignancy which leads to marrow failure, and ultimately death. There is a desperate need for new therapeutics for these patients. Ribonucleotide reductase (RR) is the rate limiting enzyme in DNA synthesis. Didox (3,4-Dihydroxybenzohydroxamic acid) is a novel RR inhibitor noted to be more potent than hydroxyurea. In this report we detail the activity and toxicity of Didox in preclinical models of AML. RR was present in all AML cell lines and primary patient samples tested. Didox was active against all human and murine AML lines tested with IC50 values in the low micromolar range (mean IC50 37 µM [range 25.89–52.70 µM]). It was active against primary patient samples at concentrations that did not affect normal hematopoietic stem cells (HSCs). Didox exposure resulted in DNA damage and p53 induction culminating in apoptosis. In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit. Didox was well tolerated, as marrow from treated animals was morphologically indistinguishable from controls. Didox exposure at levels that impaired leukemia growth did not inhibit normal HSC engraftment. In summary, Didox was well tolerated and effective against preclinical models of AML. PMID:25402485

  7. Expression Profiling of Ribosome Biogenesis Factors Reveals Nucleolin as a Novel Potential Marker to Predict Outcome in AML Patients

    PubMed Central

    Berger, Caroline M.; Perrial, Emeline; Plesa, Adriana; Thomas, Xavier; Mattei, Eve; Hayette, Sandrine; Saintigny, Pierre; Bouvet, Philippe; Diaz, Jean-Jacques; Dumontet, Charles

    2017-01-01

    Acute myeloid leukemia (AML) is a heterogeneous disease. Prognosis is mainly influenced by patient age at diagnosis and cytogenetic alterations, two of the main factors currently used in AML patient risk stratification. However, additional criteria are required to improve the current risk classification and better adapt patient care. In neoplastic cells, ribosome biogenesis is increased to sustain the high proliferation rate and ribosome composition is altered to modulate specific gene expression driving tumorigenesis. Here, we investigated the usage of ribosome biogenesis factors as clinical markers in adult patients with AML. We showed that nucleoli, the nucleus compartments where ribosome production takes place, are modified in AML by analyzing a panel of AML and healthy donor cells using immunofluorescence staining. Using four AML series, including the TCGA dataset, altogether representing a total of about 270 samples, we showed that not all factors involved in ribosome biogenesis have clinical values although ribosome biogenesis is increased in AML. Interestingly, we identified the regulator of ribosome production nucleolin (NCL) as over-expressed in AML blasts. Moreover, we found in two series that high NCL mRNA expression level was associated with a poor overall survival, particular in elderly patients. Multivariate analyses taking into account age and cytogenetic risk indicated that NCL expression in blast cells is an independent marker of reduced survival. Our study identifies NCL as a potential novel prognostic factor in AML. Altogether, our results suggest that the ribosome biogenesis pathway may be of interest as clinical markers in AML. PMID:28103300

  8. AML1/Runx1 as a versatile regulator of hematopoiesis: regulation of its function and a role in adult hematopoiesis.

    PubMed

    Kurokawa, Mineo

    2006-08-01

    AML1/Runx1, originally identified as a gene located at the breakpoint of the t(8;21) translocation, encodes a transcription factor that is widely expressed in multiple hematopoietic lineages and that regulates the expression of a variety of hematopoietic genes. Numerous studies have shown that AML1 is a critical regulator of hematopoietic development. In addition, AML1 is a frequent target for chromosomal translocation in human leukemia. The activity of AML1 can be modulated by various types of posttranslational modification, including phosphorylation and acetylation. Phosphorylation by extracellular signal-regulated kinase (ERK) is one of the mechanisms that dictate whether AML1 acts as either a transcriptional repressor or an activator of gene expression. Recently, a physiological role for AML1 in adult hematopoiesis was revealed by conditional gene targeting in mice. Remarkably, adult hematopoietic progenitors are maintained even in the absence of AML1, in stark contrast to the total disruption of definitive hematopoiesis during embryogenesis. AML1 is, however, critical for megakaryopoiesis and plays an important role in T-cell and B-cell development in adult mice. Recent analyses engineered to recreate hematopoiesis in vitro revealed that the transcriptional activity of AML1 is closely related with the potential of AML1 to generate hematopoietic cells and support thymocyte development.

  9. Expression Profiling of Ribosome Biogenesis Factors Reveals Nucleolin as a Novel Potential Marker to Predict Outcome in AML Patients.

    PubMed

    Marcel, Virginie; Catez, Frédéric; Berger, Caroline M; Perrial, Emeline; Plesa, Adriana; Thomas, Xavier; Mattei, Eve; Hayette, Sandrine; Saintigny, Pierre; Bouvet, Philippe; Diaz, Jean-Jacques; Dumontet, Charles

    2017-01-01

    Acute myeloid leukemia (AML) is a heterogeneous disease. Prognosis is mainly influenced by patient age at diagnosis and cytogenetic alterations, two of the main factors currently used in AML patient risk stratification. However, additional criteria are required to improve the current risk classification and better adapt patient care. In neoplastic cells, ribosome biogenesis is increased to sustain the high proliferation rate and ribosome composition is altered to modulate specific gene expression driving tumorigenesis. Here, we investigated the usage of ribosome biogenesis factors as clinical markers in adult patients with AML. We showed that nucleoli, the nucleus compartments where ribosome production takes place, are modified in AML by analyzing a panel of AML and healthy donor cells using immunofluorescence staining. Using four AML series, including the TCGA dataset, altogether representing a total of about 270 samples, we showed that not all factors involved in ribosome biogenesis have clinical values although ribosome biogenesis is increased in AML. Interestingly, we identified the regulator of ribosome production nucleolin (NCL) as over-expressed in AML blasts. Moreover, we found in two series that high NCL mRNA expression level was associated with a poor overall survival, particular in elderly patients. Multivariate analyses taking into account age and cytogenetic risk indicated that NCL expression in blast cells is an independent marker of reduced survival. Our study identifies NCL as a potential novel prognostic factor in AML. Altogether, our results suggest that the ribosome biogenesis pathway may be of interest as clinical markers in AML.

  10. The Hematopoietic Transcription Factor AML1 (RUNX1) Is Negatively Regulated by the Cell Cycle Protein Cyclin D3

    PubMed Central

    Peterson, Luke F.; Boyapati, Anita; Ranganathan, Velvizhi; Iwama, Atsushi; Tenen, Daniel G.; Tsai, Schickwann; Zhang, Dong-Er

    2005-01-01

    The family of cyclin D proteins plays a crucial role in the early events of the mammalian cell cycle. Recent studies have revealed the involvement of AML1 transactivation activity in promoting cell cycle progression through the induction of cyclin D proteins. This information in combination with our previous observation that a region in AML1 between amino acids 213 and 289 is important for its function led us to investigate prospective proteins associating with this region. We identified cyclin D3 by a yeast two-hybrid screen and detected AML1 interaction with the cyclin D family by both in vitro pull-down and in vivo coimmunoprecipitation assays. Furthermore, we demonstrate that cyclin D3 negatively regulates the transactivation activity of AML1 in a dose-dependent manner by competing with CBFβ for AML1 association, leading to a decreased binding affinity of AML1 for its target DNA sequence. AML1 and its fusion protein AML1-ETO have been shown to shorten and prolong the mammalian cell cycle, respectively. In addition, AML1 promotes myeloid cell differentiation. Thus, our observations suggest that the direct association of cyclin D3 with AML1 functions as a putative feedback mechanism to regulate cell cycle progression and differentiation. PMID:16287839

  11. MIT - Mighty Steps toward Energy Sustainability

    SciTech Connect

    Robinson, Alastair; Regnier, Cindy; Settlemyre, Kevin; Bosnic, Zorana

    2012-07-01

    Massachusetts Institute of Technology (MIT) partnered with the U.S. Department of Energy (DOE) to develop and implement solutions to retrofit existing buildings to reduce energy consumption by at least 30% as part of DOE’s Commercial Building Partnerships (CBP) Program.1 Lawrence Berkeley National Laboratory (LBNL) provided technical expertise in support of this DOE program. MIT is one of the U.S.’s foremost higher education institutions, occupying a campus that is nearly 100 years old, with a building floor area totaling more than 12 million square feet. The CBP project focused on improving the energy performance of two campus buildings, the Ray and Maria Stata Center (RMSC) and the Building W91 (BW91) data center. A key goal of the project was to identify energy saving measures that could be applied to other buildings both within MIT’s portfolio and at other higher education institutions. The CBP retrofits at MIT are projected to reduce energy consumption by approximately 48%, including a reduction of around 72% in RMSC lighting energy and a reduction of approximately 55% in RMSC server room HVAC energy. The energy efficiency measure (EEM) package proposed for the BW91 data center is expected to reduce heating, ventilation, and air-conditioning (HVAC) energy use by 30% to 50%, depending on the final air intake temperature that is established for the server racks. The RMSC, an iconic building designed by Frank Gehry, houses the Computer Science and Artificial Intelligence Laboratory, the Laboratory for Information and Decision Systems, and the Department of Linguistics and Philosophy.

  12. Sex disparity in childhood and young adult acute myeloid leukemia (AML) survival: Evidence from US population data.

    PubMed

    Hossain, Md Jobayer; Xie, Li

    2015-12-01

    Sex variation has been persistently investigated in studies concerning acute myeloid leukemia (AML) survival outcomes but has not been fully explored among pediatric and young adult AML patients. We detected sex difference in the survival of AML patients diagnosed at ages 0-24 years and explored distinct effects of sex across subgroups of age at diagnosis, race-ethnicity and AML subtypes utilizing the United States Surveillance Epidemiology and End Results (SEER) population based dataset of 4865 patients diagnosed with AML between 1973 and 2012. Kaplan-Meier survival function, propensity scores and stratified Cox proportional hazards regression were used for data analyses. After controlling for other prognostic factors, females showed a significant survival advantage over their male counterparts, adjusted hazard ratio (aHR, 95% confidence interval (CI): 1.09, 1.00-1.18). Compared to females, male patients had substantially increased risk of mortality in the following subgroups of: ages 20-24 years at diagnosis (aHR1.30), Caucasian (1.14), acute promyelocytic leukemia (APL) (1.35), acute erythroid leukemia (AEL) (1.39), AML with inv(16)(p13.1q22) (2.57), AML with minimum differentiation (1.47); and had substantially decreased aHR in AML t(9;11)(p22;q23) (0.57) and AML with maturation (0.82). Overall, females demonstrated increased survival over males and this disparity was considerably large in patients ages 20-24 years at diagnosis, Caucasians, and in AML subtypes of AML inv(16), APL and AEL. In contrast, males with AML t(9;11)(p22;q23), AML with maturation and age at diagnosis of 10-14 years showed survival benefit. Further investigations are needed to detect the biological processes influencing the mechanisms of these interactions.

  13. MIT Space Engineering Research Center testbed programs

    NASA Technical Reports Server (NTRS)

    Crawley, Edward F.; Miller, David W.

    1991-01-01

    The Space Engineering Research Center (SERC) at M.I.T., started in July 1988, has completed two and one-half years of research. This Semi-Annual Report presents annotated viewgraph material presented at the January 1991 Steering Committee and Technical Representative Review. The objective of the Space Engineering Research Center is to develop and disseminate a unified technology of controlled structures. There has been continued evolution of the concept of intelligent structures (including in this past year the first successful embedding of a microelectronic component into a structural element).

  14. The MIT Program, Competition, and Ethics

    NASA Astrophysics Data System (ADS)

    Bradt, Hale V.

    2013-01-01

    The MIT program in x-ray astronomy was, and still is, diverse and productive. Bruno Rossi and later George Clark, as the nominal leaders of the “x-ray astronomy group” created a “hands-off” culture wherein individual researchers could develop their own independent programs. Walter Lewin, Claude Canizares, and I as well as those in the next academic generations, e.g., Saul Rappaport and George Ricker, were able to thrive in this environment. MIT researchers were principal investigators or providers of x-ray instruments on sounding rockets and balloons in the 1960s and then in later years on nine satellite missions, OSO-7, SAS-3, HEAO-1, Einstein, ASCA, RXTE, Chandra, HETE-2, and Suzaku. Such a diverse program involved collaborations with other institutions and of course striving for primacy in discovery and competition for NASA resources. Looking back, I see a high degree of ethical behavior among the observational x-ray community during those years. In competition, we remembered that we might well be collaborating the following year and behaved accordingly. Many of us in the x-ray community had been friends since graduate school days and did not want to lose those relationships. Am I viewing the past through rose colored glasses? I think not. A vignette on this topic: In 1967, I was debating vigorously with Herb Gursky of AS&E about which institution, MIT or AS&E, should be the lead on the fourth paper (Oda et al. 1967, ApJ 148, L5) based on data from the 1966 AS&E rocket flight which had led to Allan Sandage’s (and Japanese) identification of Sco X-1 (Sandage, et al. 1966, ApJ. 146, 316). I and my Italian colleague, Gianfranco Spada, and our Japanese colleague, Minoru Oda, both then visiting MIT, had actively supported that flight. After one rather heated discussion with Herb about this, - I was the heated one; he always remained calm - he left my office saying: “Hale, however this comes out, let’s remain friends.” I treasured that comment and

  15. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML

    PubMed Central

    Krivtsov, Andrei V.; Figueroa, Maria E.; Sinha, Amit U.; Stubbs, Matthew C.; Feng, Zhaohui; Valk, Peter J.M.; Delwel, Ruud; Döhner, Konstanze; Bullinger, Lars; Kung, Andrew L.; Melnick, Ari M.; Armstrong, Scott A.

    2015-01-01

    Summary MLL-fusion proteins can induce acute myeloid leukemias (AML) from either hematopoietic stem cells (HSC) or granulocyte macrophage progenitors (GMP), but it remains unclear if the cell of origin influences the biology of the resultant leukemia. MLL-AF9 transduced single HSC or GMP could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSC or GMP had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC derived LGMP. The gene expression signature of LGMP derived from HSC was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5’-mC levels were elevated in HSC-derived leukemias as compared to GMP-derived leukemias. This mirrored a difference seen in 5-mC between MLL-rearranged human leukemias that are either EVI1-positive or EVI1-negative. Finally, HSC derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state, and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias. Significance Human AMLs are heterogeneous even within subtype defined by a specific genetic lesion such as MLL-translocations and this leads to variable clinical outcomes. The developmental stage (or epigenetic state) of the cell in which leukemogenic transformation is initiated may contribute to the ultimate disease phenotype. We used a well established model of MLL-AF9 mediated AML and transformation of single cells to test the relevance of the leukemia cell of origin on AML development, gene expression profiles, DNA methylation and chemotherapy response. We

  16. CD14 mediated endogenous TNF-alpha release in HL60 AML cells: a potential model for CD14 mediated endogenous cytokine release in the treatment of AML.

    PubMed

    Treon, S P; Anand, B; Ulevitch, R; Broitman, S A

    1994-01-01

    In previous studies, HL60 AML cells treated with tumor necrosis factor-alpha (TNF), interferon-gamma (IFN), and lipopolysaccharides (LPS) displayed decreased growth and viability, enhanced monocytic pathway differentiation and endogenous TNF release. Endogenous TNF release by LPS/TNF/IFN treated HL60 cells was postulated to play a role with the above findings. In these studies, HL60 cells expressed CD14 when treated with TNF, IFN, and LPS. CD14 mediates TNF release in monocytes/macrophages in response to binding of LPS with LPS binding protein (LBP). CD14 was not expressed in either untreated or LPS only treated HL60 cells. CD14 expression was present and greater with HL60 cells cultured with LPS/TNF/IFN vs TNF/IFN (47.47% vs 9.07% positive, respectively) suggesting synergism for LPS in CD14 induction. CD14 expression was associated with endogenous TNF release, and with significantly higher levels by HL60 cells treated with LPS/TNF/IFN vs TNF/IFN (p < 0.001). Addition of anti-CD14 antibody significantly reduced release of TNF in TNF/IFN (p < 0.001) and LPS/TNF/IFN (p = 0.0013) treated cells. KG1 and U937 AML cells treated with LPS, TNF, and IFN did not express CD14, nor release TNF. A model for inducing release of endogenous growth inhibitory cytokines by CD14 bearing AML cells is proposed as an approach to AML therapy.

  17. TET2 exon 2 skipping is an independent favorable prognostic factor for cytogenetically normal acute myelogenous leukemia (AML): TET2 exon 2 skipping in AML.

    PubMed

    Mohamed, Aminetou Mint; Balsat, Marie; Koering, Catherine; Maucort-Boulch, Delphine; Boissel, Nicolas; Payen-Gay, Lea; Cheok, Meyling; Mortada, Hussein; Auboeuf, Didier; Pinatel, Christiane; El-Hamri, Mohamed; Tigaud, Isabelle; Hayette, Sandrine; Dumontet, Charles; Cros, Emeline; Flandrin-Gresta, Pascale; Nibourel, Olivier; Preudhomme, Claude; Thomas, Xavier; Nicolini, Franck-Emmanuel; Solly, Françoise; Guyotat, Denis; Campos, Lydia; Michallet, Mauricette; Ceraulo, Antony; Mortreux, Franck; Wattel, Eric

    2017-01-16

    In AML, approximately one-third of expressed genes are abnormally spliced, including aberrant TET2 exon 2 expression. In a discovery cohort (n=99), TET2 exon 2 skipping (TET2E2S) was found positively associated with a significant reduction in the cumulative incidence of relapse (CIR). Age, cytogenetics, and TET2E2S were independent prognostic factors for disease-free survival (DFS), and favorable effects on outcomes predominated in cytogenetic normal (CN)-AML and younger patients. Using the same cutoff in a validation cohort of 86 CN-AML patients, TET2E2S(high) patients were found to be younger than TET2(low) patients without a difference in the rate of complete remission. However, TET2E2S(high) patients exhibited a significantly lower CIR (p<10(-4)). TET2E2S and FLT3-ITD, but not age or NPM1 mutation status were independent prognostic factors for DFS and event-free survival (EFS), while TET2E2S was the sole prognostic factor that we identified for overall survival (OS). In both the intermediate-1 and favorable ELN genetic categories, TET2E2S remained significantly associated with prolonged survival. There was no correlation between TET2E2S status and outcomes in 34 additional AML patients who were unfit for IC. Therefore our results suggest that assessments of TET2 exon 2 splicing status might improve risk stratification in CN-AML patients treated with IC.

  18. Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial.

    PubMed

    Quarello, Paola; Fagioli, Franca; Basso, Giuseppe; Putti, Maria C; Berger, Massimo; Luciani, Matteo; Rizzari, Carmelo; Menna, Giuseppe; Masetti, Riccardo; Locatelli, Franco

    2015-11-01

    Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and biological data, and final outcome of 48 paediatric patients with primary-resistant AML enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 clinical trial. These patients had a significantly higher white blood cell count at diagnosis compared to other AML patients. Cytogenetic and molecular features did not differ between patients with primary induction failure and patients allocated to the high-risk group. For the whole patient population, the probability of overall survival, event-free survival (EFS) and disease-free survival (DFS) was 21·8% ± 6·2, 20·4% ± 5·9, and 49·5% ± 11·3, respectively. Twenty-eight (58%) patients received haematopoietic stem cell transplantation (HSCT); 3 were autologous and 25 were allogeneic. Patients who underwent HSCT had improved EFS (31·2% vs. 5%, P < 0·0001). Only one of the 20 patients who did not receive HSCT is alive and disease free. The 19 patients in complete remission at time of HSCT showed significantly better DFS than the 9 with active disease (46% vs. 0%, P = 0·02). This study represents one of the largest series with long-term follow up of paediatric AML patients with primary refractory disease. Children who underwent transplantation had an encouraging long-term outcome. Disease recurrence remains the major cause of treatment failure; a better understanding of the disease biology is desirable to develop more effective treatment strategies.

  19. Molecular Changes During Acute Myeloid Leukemia (AML) Evolution and Identification of Novel Treatment Strategies Through Molecular Stratification.

    PubMed

    Karjalainen, E; Repasky, G A

    2016-01-01

    Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by impaired differentiation and uncontrollable proliferation of myeloid progenitor cells. Due to high relapse rates, overall survival for this rapidly progressing disease is poor. The significant challenge in AML treatment is disease heterogeneity stemming from variability in maturation state of leukemic cells of origin, genetic aberrations among patients, and existence of multiple disease clones within a single patient. Disease heterogeneity and the lack of biomarkers for drug sensitivity lie at the root of treatment failure as well as selective efficacy of AML chemotherapies and the emergence of drug resistance. Furthermore, standard-of-care treatment is aggressive, presenting significant tolerability concerns to the commonly advanced-age AML patient. In this review, we examine the concept and potential of molecular stratification, particularly with biologically relevant drug responses, in identifying low-toxicity precision therapeutic combinations and clinically relevant biomarkers for AML patient care as a way to overcome these challenges in AML treatment.

  20. Trisomy 8 in pediatric acute myeloid leukemia: A NOPHO-AML study.

    PubMed

    Laursen, Anne Cathrine Lund; Sandahl, Julie Damgaard; Kjeldsen, Eigil; Abrahamsson, Jonas; Asdahl, Peter; Ha, Shau-Yin; Heldrup, Jesper; Jahnukainen, Kirsi; Jónsson, Ólafur G; Lausen, Birgitte; Palle, Josefine; Zeller, Bernward; Forestier, Erik; Hasle, Henrik

    2016-09-01

    Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone. © 2016 Wiley Periodicals, Inc.

  1. A stable transcription factor complex nucleated by oligomeric AML1–ETO controls leukaemogenesis

    SciTech Connect

    Sun, Xiao-Jian; Wang, Zhanxin; Wang, Lan; Jiang, Yanwen; Kost, Nils; Soong, T. David; Chen, Wei-Yi; Tang, Zhanyun; Nakadai, Tomoyoshi; Elemento, Olivier; Fischle, Wolfgang; Melnick, Ari; Patel, Dinshaw J.; Nimer, Stephen D.; Roeder, Robert G.

    2013-06-30

    Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression. AML1–ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation. AML1–ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis, making it important to identify co-regulatory factors that ‘read’ the NHR2 oligomerization and contribute to leukaemogenesis. Here we show that, in human leukaemic cells, AML1–ETO resides in and functions through a stable AML1–ETO-containing transcription factor complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, co-localize genome wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1–ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2–N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1–ETO-induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1–ETO, and provide a potential therapeutic target in t(8;21)-positive acute myeloid leukaemia.

  2. Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by Toll-like receptor (TLR) agonists

    PubMed Central

    Zhong, RuiKun; Li, Hongying; Messer, Karen; Lane, Thomas A.; Zhou, Jiehua; Ball, Edward D.

    2016-01-01

    This study investigated whether TNF-α, Toll-like receptors (TLRs) 7/8 agonist resiquimod (R848), the TLR4 agonist lipopolysaccharide (LPS) and their combinations can enhance autologous AML-reactive T cell generation in an in vitro culture. AML peripheral blood or bone marrow mononuclear cells were cultured in medium supplemented with GM-CSF/IL-4 to induce dendritic cell (DC) differentiation of AML blasts (AML-DC). The impact of TNF-α, LPS, R848 and their combinations on AML-DC cultures was analyzed. Significantly enhanced CD80, CD40, CD83, CD54, HLADR and CD86 expression of AML cells was observed by addition of TNF-α, LPS, R848 alone or combinations. Induced CD80 expression of AML cells was significantly higher through the combination of TNF-α, LPS and R848 (T + L + R) than that by T alone. CTL induced from T + L + R, T + R, T + L, L + R and R, but not T, L alone stimulated cultures showed significantly higher IFN-γ release than the medium control in response to autologous AML cells. IFN-γ release by T + L + R was significantly higher than T or L alone, and T + R was significantly higher than T alone. CTL generated from T + L + R, T + L, T + R, L + R and L alone exerted significantly higher AML cell killing than medium control. AML cell killing by T + L + R and T + R was significantly higher than T or R alone. These results indicate that the combination of T + L + R induces a significantly enhanced antigen presentation effect of AML-DC. We speculate that the complementary effects of reagent combinations may better address the heterogeneity of responses to any single agent in AML cells from different patients. PMID:25795133

  3. MMPI and MIT Discriminators of Biogenic and Psychogenic Impotence

    ERIC Educational Resources Information Center

    Beutler, Larry E.; And Others

    1975-01-01

    Male patients complaining of impotence (N=32) were administered the Male Impotence Test (MIT) and the Minnesota Multiphasic Personality Inventory (MMPI). The results suggested that the MIT is without value for differentiating between psychogenic and biogenic impotence, whereas two rules from the MMPI appropriately classified 90 percent of the…

  4. MMPI and MIT Discriminators of Biogenic and Psychogenic Impotence

    ERIC Educational Resources Information Center

    Beutler, Larry E.; And Others

    1975-01-01

    Male patients complaining of impotence (N=32) were administered the Male Impotence Test (MIT) and the Minnesota Multiphasic Personality Inventory (MMPI). The results suggested that the MIT is without value for differentiating between psychogenic and biogenic impotence, whereas two rules from the MMPI appropriately classified 90 percent of the…

  5. Physik gestern und heute: Visualisierung mit der Schlierenmethode

    NASA Astrophysics Data System (ADS)

    Heering, Peter

    2006-07-01

    Der Name des österreichischen Forschers Ernst Mach ist heute noch mit der Schallgeschwindigkeit verbunden. Diese Auszeichnung resultiert aus Machs Untersuchungen, wie sich Projektile mit Überschallgeschwindigkeit durch die Luft bewegen. Gerade in jüngster Zeit hat die Anwendung derartiger Methoden durch technische Modifikationen wieder einen Aufschwung erfahren.

  6. Cellular Reprogramming Allows Generation of Autologous Hematopoietic Progenitors From AML Patients That Are Devoid of Patient-Specific Genomic Aberrations.

    PubMed

    Salci, Kyle R; Lee, Jong-Hee; Laronde, Sarah; Dingwall, Steve; Kushwah, Rahul; Fiebig-Comyn, Aline; Leber, Brian; Foley, Ronan; Dal Cin, Arianna; Bhatia, Mickie

    2015-06-01

    Current treatments that use hematopoietic progenitor cell (HPC) transplantation in acute myeloid leukemia (AML) patients substantially reduce the risk of relapse, but are limited by the availability of immune compatible healthy HPCs. Although cellular reprogramming has the potential to provide a novel autologous source of HPCs for transplantation, the applicability of this technology toward the derivation of healthy autologous hematopoietic cells devoid of patient-specific leukemic aberrations from AML patients must first be evaluated. Here, we report the generation of human AML patient-specific hematopoietic progenitors that are capable of normal in vitro differentiation to myeloid lineages and are devoid of leukemia-associated aberration found in matched patient bone marrow. Skin fibroblasts were obtained from AML patients whose leukemic cells possessed a distinct, leukemia-associated aberration, and used to create AML patient-specific induced pluripotent stem cells (iPSCs). Through hematopoietic differentiation of AML patient iPSCs, coupled with cytogenetic interrogation, we reveal that AML patient-specific HPCs possess normal progenitor capacity and are devoid of leukemia-associated mutations. Importantly, in rare patient skin samples that give rise to mosaic fibroblast cultures that continue to carry leukemia-associated mutations; healthy hematopoietic progenitors can also be generated via reprogramming selection. Our findings provide the proof of principle that cellular reprogramming can be applied on a personalized basis to generate healthy HPCs from AML patients, and should further motivate advances toward creating transplantable hematopoietic stem cells for autologous AML therapy.

  7. Consolidation with autologous stem cell transplantation in first remission is safe and effective in AML patients above 65 years.

    PubMed

    Heini, Alexander D; Berger, Martin D; Seipel, Katja; Taleghani, Behrouz Mansouri; Baerlocher, Gabriela M; Leibundgut, Kurt; Banz, Yara; Novak, Urban; Pabst, Thomas

    2017-02-01

    The outcome of AML patients ≥65 years remains disappointing. Current post-induction strategies for elderly AML patients fit for intensive treatment involve additional cycles of chemotherapy or allogeneic transplantation. Consolidation with autologous transplantation (ASCT) is poorly studied in these patients. In this single-center retrospective analysis, we determined survival rates of AML patients ≥65 years undergoing busulfan/cyclophosphamide conditioning before ASCT in first remission between 2007 and 2015. We found elderly AML patients with ASCT to have longer progression-free survival (PFS; 16.3 vs. 5.1 months, P=0.0166) and overall survival (OS; n.r. vs. 8.2 months; P=0.0255) than elderly AML patients without ASCT consolidation. In addition, elderly AML patients undergoing ASCT had comparable PFS (P=0.9462) and OS (P=0.7867) as AML patients below 65 years receiving ASCT consolidation in CR1. Our data suggest that ASCT is an option in elderly fit AML patients who appear to benefit from autologous consolidation similarly to younger AML patients.

  8. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells.

    PubMed

    Fiskus, W; Sharma, S; Shah, B; Portier, B P; Devaraj, S G T; Liu, K; Iyer, S P; Bearss, D; Bhalla, K N

    2014-11-01

    The histone demethylase LSD1 (KDM1A) demethylates mono- and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in acute myeloid leukemia (AML). Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and CCAAT/enhancer binding protein α in cultured AML cells. In addition, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphological features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than mixed-lineage leukemia fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Co-treatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared with each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML.

  9. An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms.

    PubMed Central

    Tanaka, T; Tanaka, K; Ogawa, S; Kurokawa, M; Mitani, K; Nishida, J; Shibata, Y; Yazaki, Y; Hirai, H

    1995-01-01

    The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22) translocations associated with myelogenous leukemias and encodes a DNA binding protein. From the AML1 gene, two representative forms of proteins, AML1a and AML1b, are produced by alternative splicing. Both forms have a DNA binding domain but, unlike AML1b, AML1a lacks a putative transcriptional activation domain. Here we demonstrate that overexpressed AML1a totally suppresses granulocytic differentiation and stimulates cell proliferation in 32Dcl3 murine myeloid cells treated with granulocyte colony-stimulating factor. These effects of AML1a were canceled by the concomitant overexpression of AML1b. Such biological phenomena could be explained by our observations that (i) AML1a, which on its own has no effects as a transcriptional regulator, dominantly suppresses transcriptional activation by AML1b, and (ii) AML1a exhibits the higher affinity for DNA binding compared with AML1b. These antagonistic actions could be important in leukemogenesis and/or myeloid cell differentiation because more than half of myelogenous leukemia patients showed an increase in the relative amounts of AML1a. Images PMID:7530657

  10. Implementation of Microfiche Image Transmission System (MITS): A multifaceted assessment of demonstration installation

    NASA Astrophysics Data System (ADS)

    Sheposh, J. P.; Hulton, V. N.

    1983-06-01

    A multifaceted approach was employed to evaluate the introduction and implementation of a technological system--the microfiche image transmission system (MITS). Four different aspects of the demonstration installation were investigated: (1) operators' perception of MITS, (2) the requesters' acceptance of the services provided, (3) image quality, and (4) management's evaluation of the MITS implementation. The results revealed that the operators' perceptions of MITS were positive, the requesters regarded MITS as highly satisfactory, the image quality of the facsimile input fiche was judged superior to the MITS output, and the managers and developers regarded the MITS implementation as a success. Issues concerning widespread application of MITS were seen as premature at this time.

  11. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes.

    PubMed

    Huan, J; Hornick, N I; Goloviznina, N A; Kamimae-Lanning, A N; David, L L; Wilmarth, P A; Mori, T; Chevillet, J R; Narla, A; Roberts, C T; Loriaux, M M; Chang, B H; Kurre, P

    2015-12-01

    We recently demonstrated that acute myeloid leukemia (AML) cell lines and patient-derived blasts release exosomes that carry RNA and protein; following an in vitro transfer, AML exosomes produce proangiogenic changes in bystander cells. We reasoned that paracrine exosome trafficking may have a broader role in shaping the leukemic niche. In a series of in vitro studies and murine xenografts, we demonstrate that AML exosomes downregulate critical retention factors (Scf, Cxcl12) in stromal cells, leading to hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow. Exosome trafficking also regulates HSPC directly, and we demonstrate declining clonogenicity, loss of CXCR4 and c-Kit expression, and the consistent repression of several hematopoietic transcription factors, including c-Myb, Cebp-β and Hoxa-9. Additional experiments using a model of extramedullary AML or direct intrafemoral injection of purified exosomes reveal that the erosion of HSPC function can occur independent of direct cell-cell contact with leukemia cells. Finally, using a novel multiplex proteomics technique, we identified candidate pathways involved in the direct exosome-mediated modulation of HSPC function. In aggregate, this work suggests that AML exosomes participate in the suppression of residual hematopoietic function that precedes widespread leukemic invasion of the bone marrow directly and indirectly via stromal components.

  12. Telomere length is an independent prognostic marker in MDS but not in de novo AML.

    PubMed

    Williams, Jenna; Heppel, Nicole H; Britt-Compton, Bethan; Grimstead, Julia W; Jones, Rhiannon E; Tauro, Sudhir; Bowen, David T; Knapper, Steven; Groves, Michael; Hills, Robert K; Pepper, Chris; Baird, Duncan M; Fegan, Chris

    2017-07-01

    Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication-mutated AML patients (P = 0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81 kb) did not provide prognostic resolution in AML [Hazard ratio (HR) = 0·68, P = 0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR = 5·0, P < 0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR = 2·27, P < 0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS. © 2017 John Wiley & Sons Ltd.

  13. Initiation of MLL-rearranged AML is dependent on C/EBPα

    PubMed Central

    Ohlsson, Ewa; Hasemann, Marie Sigurd; Willer, Anton; Lauridsen, Felicia Kathrine Bratt; Rapin, Nicolas; Jendholm, Johan

    2014-01-01

    MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL–induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion–driven transformation and find that it sharply demarcates tumor initiation and maintenance. PMID:24367003

  14. A standardized microarray assay for the independent gene expression markers in AML: EVI1 and BAALC.

    PubMed

    Brand, Jaap; van Vliet, Martin H; de Best, Leonie; Valk, Peter Jm; Viëtor, Henk E; Löwenberg, Bob; van Beers, Erik H

    2013-03-06

    High levels of BAALC, ERG, EVI1 and MN1 expression have been associated with shorter overall survival in AML but standardized and clinically validated assays are lacking. We have therefore developed and optimized an assay for standardized detection of these prognostic genes for patients with intermediate cytogenetic risk AML. In a training set of 147 intermediate cytogenetic risk cases we performed cross validations at 5 percentile steps of expression level and observed a bimodal significance profile for BAALC expression level and unimodal significance profiles for ERG and MN1 levels with no statistically significant cutoff points near the median expression level of BAALC, ERG or MN1. Of the possible cutoff points for expression levels of BAALC, ERG and MN1, just the 30th and 75th percentile of BAALC expression level and the 30th percentile of MN1 expression level cutoff points showed clinical significance. Of these only the 30th percentile of BAALC expression level reproduced in an independent verification (extended training) data set of 242 cytogenetically normal AML cases and successfully validated in an external cohort of 215 intermediate cytogenetic risk AML cases. Finally, we show independent prognostic value for high EVI1 and low BAALC in multivariate analysis with other clinically relevant molecular AML markers. We have developed a highly standardized molecular assay for the independent gene expression markers EVI1 and BAALC.

  15. Age-related epigenetic drift in the pathogenesis of MDS and AML.

    PubMed

    Maegawa, Shinji; Gough, Sheryl M; Watanabe-Okochi, Naoko; Lu, Yue; Zhang, Nianxiang; Castoro, Ryan J; Estecio, Marcos R H; Jelinek, Jaroslav; Liang, Shoudan; Kitamura, Toshio; Aplan, Peter D; Issa, Jean-Pierre J

    2014-04-01

    The myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylation in the bone marrow and spleen in two mouse models of MDS/AML, the NUP98-HOXD13 (NHD13) mouse and the RUNX1 mutant mouse model. Methylation array analysis showed an average of 512/3445 (14.9%) genes hypermethylated in NHD13 MDS, and 331 (9.6%) genes hypermethylated in RUNX1 MDS. Thirty-two percent of genes in common between the two models (2/3 NHD13 mice and 2/3 RUNX1 mice) were also hypermethylated in at least two of 19 human MDS samples. Detailed analysis of 41 genes in mice showed progressive drift in DNA methylation from young to old normal bone marrow and spleen; to MDS, where we detected accelerated age-related methylation; and finally to AML, which markedly extends DNA methylation abnormalities. Most of these genes showed similar patterns in human MDS and AML. Repeat element hypomethylation was rare in MDS but marked the transition to AML in some cases. Our data show consistency in patterns of aberrant DNA methylation in human and mouse MDS and suggest that epigenetically, MDS displays an accelerated aging phenotype.

  16. Survival benefits with transplantation in secondary AML evolving from myelodysplastic syndrome with hypomethylating treatment failure.

    PubMed

    Shin, S-H; Yahng, S-A; Yoon, J-H; Lee, S-E; Cho, B-S; Eom, K-S; Lee, S; Min, C-K; Kim, H-J; Cho, S-G; Kim, D-W; Lee, J-W; Min, W-S; Park, C-W; Kim, Y-J

    2013-05-01

    The prognosis for patients with myelodysplastic syndrome with hypomethylating treatment failure (MDS-HTF) has been known to be poor. However, the clinical outcomes and optimal treatment options for secondary AML evolving from MDS-HTF (sAML/MDS-HTF) are not well known. This retrospective analysis was conducted to evaluate the clinical outcomes and influences of treatment options on survival in 46 consecutive patients with sAML/MDS-HTF. The median OS rates were 1.4 months in the best supportive care group (n=15) and 9.4 months in the active treatment group (n=31). One-year OS rates were 13.3% and 36.8%, respectively (P=0.001). Active treatment (P<0.001), lower BM blast (<33%) at sAML (P=0.007), non-poor NCCN (National Cancer Comprehensive Network) cytogenetics (P=0.001) and good performance status (ECOG (Eastern Cooperative Oncology Group) 1) (P=0.024) were significant predictors affecting favorable OS in a multivariate analysis. Of the active treatment options, allo-SCT with prior chemotherapy (CTx) showed better OS compared with CTx only or SCT without CTx (P=0.019). Our analyses suggest that active treatment, particularly SCT following CTx, should be considered in patients with sAML/MDS-HTF if the patient is medically fit.

  17. Oncogene- and drug resistance-associated alternative exon usage in acute myeloid leukemia (AML)

    PubMed Central

    Mohamed, Aminetou Mint; Balsat, Marie; Thenoz, Morgan; Koering, Catherine; Payen-Gay, Lea; Cheok, Meyling; Mortada, Hussein; Auboeuf, Didier; Pinatel, Christiane; El-Hamri, Mohamed; Dumontet, Charles; Cros, Emeline; Flandrin-Gresta, Pascale; Nibourel, Olivier; Preudhomme, Claude; Michallet, Mauricette; Thomas, Xavier; Nicolini, Franck; Solly, Françoise; Guyotat, Denis; Campos, Lydia

    2016-01-01

    In addition to spliceosome gene mutations, oncogene expression and drug resistance in AML might influence exon expression. We performed exon-array analysis and exon-specific PCR (ESPCR) to identify specific landscapes of exon expression that are associated with DEK and WT1 oncogene expression and the resistance of AML cells to AraC, doxorubicin or azacitidine. Data were obtained for these five conditions through exon-array analysis of 17 cell lines and 24 patient samples and were extended through qESPCR of samples from 152 additional AML cases. More than 70% of AEUs identified by exon-array were technically validated through ESPCR. In vitro, 1,130 to 5,868 exon events distinguished the 5 conditions from their respective controls while in vivo 6,560 and 9,378 events distinguished chemosensitive and chemoresistant AML, respectively, from normal bone marrow. Whatever the cause of this effect, 30 to 80% of mis-spliced mRNAs involved genes unmodified at the whole transcriptional level. These AEUs unmasked new functional pathways that are distinct from those generated by transcriptional deregulation. These results also identified new putative pathways that could help increase the understanding of the effects mediated by DEK or WT1, which may allow the targeting of these pathways to prevent resistance of AML cells to chemotherapeutic agents. PMID:26284582

  18. Unfälle mit Kleintransportern

    NASA Astrophysics Data System (ADS)

    Tschirschwitz, Christian

    Auf einer außerörtlichen Bundesstraße geriet ein mit vier Personen besetzter Pkw Toyota Corolla aus letztlich nicht vollständig geklärten Gründen ins Schleudern. Nachdem sich das Fahrzeug beträchtlich entgegen dem Uhrzeigersinn ausgedreht hatte, prallte ein entgegenkommender Kleintransporter VW T4 frontal an die rechte Flanke des Toyota. Der Transporter wurde gedreht, ausgehoben und durch einen Pkw Ford Escort unterfahren. Alle Fahrzeuge kamen in Kollisionsortnähe zum Endstand. Die vier Toyota-Insassen wurden getötet. Aus den anderen Fahrzeugen wurden sechs Personen überwiegend schwer verletzt. Unbeteiligte Zeugen waren nicht vorhanden.

  19. The MIT short-wavelength laser project

    NASA Astrophysics Data System (ADS)

    Hagelstein, P.; Basu, S.; Muendel, M.; Braud, J. P.; Kaushik, S.; Tauber, D.

    The present status of the project follows: the Nd:glass power amplifier was constructed and brought from LLNL to MIT; gain measurements were performed, and work on the associated optics is currently underway. The vacuum chamber was built and successfully tested. The optics for the target alignment system were redesigned, fabricated, and partially assembled; the electronics are now being brought together. EUV spectrometers for use as laser diagnostics are under development; these incorporate both commercially available gratings as well as novel, in-house designs. Work on laser cavities has yielded an greatly improved understanding of the difficulties involved in using whispering gallery optics. An earlier analysis of soft x ray frequency conversion was refined. A numerical study of plasma kinetics has elucidated the physics of transiently pumped x ray lasers.

  20. Unfälle mit Kleintransportern

    NASA Astrophysics Data System (ADS)

    Tschirschwitz, Christian

    Auf einer außerörtlichen Bundesstraße geriet ein mit vier Personen besetzter Pkw Toyota Corolla aus letztlich nicht vollständig geklärten Gründen ins Schleudern. Nachdem sich das Fahrzeug beträchtlich entgegen dem Uhrzeigersinn ausgedreht hatte, prallte ein entgegenkommender Kleintransporter VW T4 frontal an die rechte Flanke des Toyota. Der Transporter wurde gedreht, ausgehoben und durch einen Pkw Ford Escort unterfahren. Alle Fahrzeuge kamen in Kollisionsortnähe zum Endstand. Die vier Toyota-Insassen wurden getötet. Aus den anderen Fahrzeugen wurden sechs Personen überwiegend schwer verletzt. Unbeteiligte Zeugen waren nicht vorhanden.

  1. MIT microwiggler for free electron laser applications

    SciTech Connect

    Catravas, P.; Stoner, R.; Blastos, J.; Sisson, D.; Mastovsky, I.; Bekefi, G.; Wang, X.J.; Fisher, A.

    1995-07-01

    A microwiggler-based FEL permits operation at shorter wavelengths with a reduction in the size and cost of the device. The MIT microwiggler is a pulsed ferromagnetic-core electromagnet with 70 periods of 8.8 mm each which generates an on-axis peak magnetic field of 4.2 kG. The pulse repetition rate is 0.5 Hz with FWHM 0.5 msec. The microwiggler is characterized by extensive tunability. We employed a novel tuning regimen through which the rms spread in peak amplitudes was reduced to 0.08 % the lowest ever achieved in a sub-cm period magnetic field. The microwiggler is a serviceable scientific apparatus: spontaneous emission has been observed for wavelengths of 700--800 nm using a 40 MeV beam from the Accerator Test Facility LINAC at BNL.

  2. Teaching ``The Physics of Energy'' at MIT

    NASA Astrophysics Data System (ADS)

    Jaffe, Robert

    2009-05-01

    New physics courses on energy are popping up at colleges and universities across the country. Many require little or no previous physics background, aiming to introduce a broad audience to this complex and critical problem, often augmenting the scientific message with economic and policy discussions. Others are advanced courses, focussing on highly specialized subjects like solar voltaics, nuclear physics, or thermal fluids, for example. About two years ago Washington Taylor and I undertook to develop a course on the ``Physics of Energy'' open to all MIT students who had taken MIT's common core of university level calculus, physics, and chemistry. By avoiding higher level prerequisites, we aimed to attract and make the subject relevant to students in the life sciences, economics, etc. --- as well as physical scientists and engineers --- who want to approach energy issues in a sophisticated and analytical fashion, exploiting their background in calculus, mechanics, and E & M, but without having to take advanced courses in thermodynamics, quantum mechanics, or nuclear physics beforehand. Our object was to interweave teaching the fundamental physics principles at the foundations of energy science with the applications of those principles to energy systems. We envisioned a course that would present the basics of statistical, quantum, and fluid mechanics at a fairly sophisticated level and apply those concepts to the study of energy sources, conversion, transport, losses, storage, conservation, and end use. In the end we developed almost all of the material for the course from scratch. The course debuted this past fall. I will describe what we learned and what general lessons our experience might have for others who contemplate teaching energy physics broadly to a technically sophisticated audience.

  3. Dual-fuel versus single-fuel propulsion systems for AMLS applications. [Advanced Manned Launch System

    NASA Technical Reports Server (NTRS)

    Stanley, Douglas O.; Talay, T. A.

    1989-01-01

    The results of using a computerized preliminary design system to integrate propulsion systems examined as a part of the Space Transportation Main Engine (STME) and Space Transportation Booster Engine (STBE) studies with reference vehicle concepts from the Advanced Manned Launch System (AMLS) study are presented. The major trade study presented is an analysis of the effect of using a single fuel for both stages of two-stage AMLS reference vehicles as opposed to using a separate fuel for the boosters. Other trade studies presented examine the effect of varying relevant engine parameters in an attempt to optimize the reference engines for use with the AMLS launch vehicles. In each propulsion trade discussed, special attention is given to the major vehicle performance and operational issues involved.

  4. Donor lymphocyte infusions in AML and MDS: Enhancing the graft-versus-leukemia effect.

    PubMed

    Orti, Guillermo; Barba, Pere; Fox, Laura; Salamero, Olga; Bosch, Francesc; Valcarcel, David

    2017-04-01

    Allogeneic hematopoietic cell transplantation (allo-HCT) represents the only curative therapy for many haematological malignancies. Its curative potential is mostly attributed to the graft-versus-leukemia effect (GvL), which is mainly driven by donor T-cells. Donor lymphocyte infusions (DLI), likewise a second allo-HCT, have become a standard approach to treat AML and MDS relapses post allo-HCT. Although DLI have been used in this setting for decades, its effectivity and toxicity are still unpredictable in many patients. Over these recent years, new DLI strategies and therapies have been developed for AML and MDS. In this review, we will overview the recent use of DLI for AML and MDS, with up to date information from novel studies and research lines.

  5. Clinical significance of in vivo cytarabine-induced gene expression signature in AML.

    PubMed

    Lamba, Jatinder K; Pounds, Stanley; Cao, Xueyuan; Crews, Kristine R; Cogle, Christopher R; Bhise, Neha; Raimondi, Susana C; Downing, James R; Baker, Sharyn D; Ribeiro, Raul C; Rubnitz, Jeffrey E

    2016-01-01

    Despite initial remission, ∼60-70% of adult and 30% of pediatric patients experience relapse or refractory AML. Studies so far have identified base line gene expression profiles of pathogenic and prognostic significance in AML; however, the extent of change in gene expression post-initiation of treatment has not been investigated. Exposure of leukemic cells to chemotherapeutic agents such as cytarabine, a mainstay of AML chemotherapy, can trigger adaptive response by influencing leukemic cell transcriptome and, hence, development of resistance or refractory disease. It is, however, challenging to perform such a study due to lack of availability of specimens post-drug treatment. The primary objective of this study was to identify in vivo cytarabine-induced changes in leukemia cell transcriptome and to evaluate their impact on clinical outcome. The results highlight genes relevant to cytarabine resistance and support the concept of targeting cytarabine-induced genes as a means of improving response.

  6. Prognostic factors of childhood and adolescent acute myeloid leukemia (AML) survival: evidence from four decades of US population data.

    PubMed

    Hossain, Md Jobayer; Xie, Li; Caywood, Emi H

    2015-10-01

    Growing insight into prognosis of pediatric acute myeloid leukemia (AML) survival has led to improved outcome over time and could be further enhanced through investigation using a large number of patients. To characterize the extent of the association of pediatric AML survival with its identified prognostic factors, we analyzed the United States population-based Surveillance Epidemiology and End Results (SEER) large dataset of 3442 pediatric AML patients diagnosed and followed between 1973 and 2011 using a Cox proportional hazards model stratified by year of diagnosis. Patients diagnosed between 10 and 19 years of age were at a higher risk of death compared to those diagnosed before age 10 (adjusted hazard ratio (aHR): 1.30, 95% confidence interval (CI): 1.17-1.44). African Americans (1.27, 1.09-1.48) and Hispanics (1.15, 1.00-1.32) had an elevated risk of mortality than Caucasians. Compared to the subtype acute promyelocytic leukemia, AML with minimal differentiation (2.44, 1.78-3.35); acute erythroid leukemia (2.34, 1.60-3.40); AML without maturation (1.87, 1.35-2.59); and most other AML subtypes had a higher risk of mortality, whereas AML with inv(16) had a substantially lower risk. Age at diagnosis, race-ethnicity, AML subtype, county level poverty and geographic region appeared as significant prognostic factors of pediatric AML survival in the US. Contrary to previous findings, the subtypes of AML with t(9;11)(p22;q23)MLLT3-MLL, AML without maturation and acute myelomonocytic leukemia emerged to be indicative of poor outcome.

  7. Targeting PI3Kδ and PI3Kγ signalling disrupts human AML survival and bone marrow stromal cell mediated protection.

    PubMed

    Pillinger, Genevra; Loughran, Niamh V; Piddock, Rachel E; Shafat, Manar S; Zaitseva, Lyubov; Abdul-Aziz, Amina; Lawes, Matthew J; Bowles, Kristian M; Rushworth, Stuart A

    2016-06-28

    Phosphoinositide-3-kinase (PI3K) is an enzyme group, known to regulate key survival pathways in acute myeloid leukaemia (AML). It generates phosphatidylinositol-3,4,5-triphosphate, which provides a membrane docking site for protein kinaseB activation. PI3K catalytic p110 subunits are divided into 4 isoforms; α,β,δ and γ. The PI3Kδ isoform is always expressed in AML cells, whereas the frequency of PI3Kγ expression is highly variable. The functions of these individual catalytic enzymes have not been fully resolved in AML, therefore using the PI3K p110δ and p110γ-targeted inhibitor IPI-145 (duvelisib) and specific p110δ and p110γ shRNA, we analysed the role of these two p110 subunits in human AML blast survival. The results show that PI3Kδ and PI3Kγ inhibition with IPI-145 has anti-proliferative activity in primary AML cells by inhibiting the activity of AKT and MAPK. Pre-treatment of AML cells with IPI-145 inhibits both adhesion and migration of AML blasts to bone marrow stromal cells. Using shRNA targeted to the individual isoforms we demonstrated that p110δ-knockdown had a more significant anti-proliferative effect on AML cells, whereas targeting p110γ-knockdown significantly inhibited AML migration. The results demonstrate that targeting both PI3Kδ and PI3Kγ to inhibit AML-BMSC interactions provides a biologic rationale for the pre-clinical evaluation of IPI-145 in AML.

  8. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML.

    PubMed

    DiNardo, Courtney D; Ravandi, Farhad; Agresta, Sam; Konopleva, Marina; Takahashi, Koichi; Kadia, Tapan; Routbort, Mark; Patel, Keyur P; Mark Brandt; Pierce, Sherry; Garcia-Manero, Guillermo; Cortes, Jorge; Kantarjian, Hagop

    2015-08-01

    The pathophysiology of IDH mutations in tumorigenesis is increasingly described, yet the prognostic significance of IDH1 and IDH2 mutations in AML remains controversial. The primary objective of this study was to define the natural history and prognosis of patients with AML and IDH1 or IDH2 mutations and provide historical survival expectations. A total of 826 patients treated from 2010 to 2014 at a single institution were evaluated, including 167 patients (20%) with AML and IDH1 or IDH2 mutations. Median age was 62 years (range 18-92). There were 59 IDH1-R132, 83 IDH2-R140, and 23 IDH2-R172 mutations. Clinicopathologic characteristics associated with IDH-mutations included older age, less frequent therapy-related status, and increased incidence of intermediate-risk cytogenetics, FLT3-ITD mutations, and NPM1 mutations. Remission rates (CR/CRi) by AML treatment status were: induction, 68%; Salvage-1 (S1), 42%; and Salvage-2 and beyond (S2+), 27%. No difference in response was identified by IDH mutation status. Similarly, overall survival (OS) was not dependent on IDH status within any cohort. The median OS was 15.4 months in induction, 8.7 months in S1, and 4.8 months in S2+. This analysis defines the clinical outcome associated with IDH-mutations in both the front-line and salvage AML treatment settings, and confirms that response rate and OS for both IDH-mutated and IDH wild-type AML patients is comparable. This provides contemporary data to be used for comparison with results of novel investigational (e.g., selective IDH inhibitor) strategies.

  9. Comparison of Calorimetry: MIT and Fleischmann-Pons Systems

    NASA Astrophysics Data System (ADS)

    Miles, Melvin H.; Hagelstein, Peter

    2011-03-01

    The history of cold fusion shows that the MIT heat conduction calorimetry in 1990 reported a sensitivity of 40 mW while the Fleischmann-Pons Dewar calorimetry achieved a sensitivity of 0.1 mW. Additional information about the MIT calorimetry allows a more detailed analysis. The major finding is that the MIT calorimetric cell was so well insulated with glass wool (2.5 cm in thickness) that the major heat transport pathway was out of the cell top rather than from the cell into the constant temperature water bath. It can be shown for the MIT calorimeter that 58% of the heat transport was through the cell top and 42% was from the cell into the water bath. Analysis of the Fleischmann-Pons Dewar cell shows that under conditions similar to the MIT experiments, almost all of the heat flow would be from the Dewar calorimetric cell to the constant temperature water bath. Furthermore, the sensitivity of the Fleischmann- Pons temperature measurements was 0.001 K versus 0.1 K for the MIT calorimetric cell. Evaluations of the calorimetric equations and data analysis methods leads to the conclusion that the Fleischmann-Pons calorimetry was far superior to that of MIT.

  10. Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: the runt homology domain is required for DNA binding and protein-protein interactions.

    PubMed Central

    Meyers, S; Downing, J R; Hiebert, S W

    1993-01-01

    The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) translocation associated with acute myelogenous leukemia and encodes a protein with a central 118-amino-acid domain with 69% homology to the Drosophila pair-rule gene, runt. We demonstrate that AML-1 is a DNA-binding protein which specifically interacts with a sequence belonging to the group of enhancer core motifs, TGT/cGGT. Electrophoretic mobility shift analysis of cell extracts identified two AML-1-containing protein-DNA complexes whose electrophoretic mobilities were slower than those of complexes formed with AML-1 produced in vitro. Mixing of in vitro-produced AML-1 with cell extracts prior to gel mobility shift analysis resulted in the formation of higher-order complexes. Deletion mutagenesis of AML-1 revealed that the runt homology domain mediates both sequence-specific DNA binding and protein-protein interactions. The hybrid product, AML-1/ETO, which results from the (8;21) translocation and retains the runt homology domain, both recognizes the AML-1 consensus sequence and interacts with other cellular proteins. Images PMID:8413232

  11. An Implementation and Evaluation of the AMLS Method for SparseEigenvalue Problems

    SciTech Connect

    Gao, Weiguo; Li, Xiaoye S.; Yang, Chao; Bai, Zhaojun

    2006-02-14

    We describe an efficient implementation and present aperformance study of an algebraic multilevel sub-structuring (AMLS)method for sparse eigenvalue problems. We assess the time and memoryrequirements associated with the key steps of the algorithm, and compareitwith the shift-and-invert Lanczos algorithm in computational cost. Oureigenvalue problems come from two very different application areas: theaccelerator cavity design and the normal mode vibrational analysis of thepolyethylene particles. We show that the AMLS method, when implementedcarefully, is very competitive with the traditional method in broadapplication areas, especially when large numbers of eigenvalues aresought.

  12. MINIMAL RESIDUAL DISEASE IN AML: WHY HAS IT LAGGED BEHIND PEDIATRIC ALL?

    PubMed Central

    Paietta, Elisabeth

    2015-01-01

    Although the concept of minimal residual disease (MRD) as an indicator for the quality of treatment response is the same in acute myeloid (AML) and acute lymphoid leukemia (ALL), the practice of measuring MRD levels for monitoring response and guiding post-induction therapy has been implemented much more rapidly in ALL, particularly pediatric ALL, than in AML. This perspective will look at the facts and discuss why ALL appears to be more amenable to MRD-shaped risk-allocation and a revised definition of complete remission. PMID:26297274

  13. Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML.

    PubMed

    Dany, Mohammed; Gencer, Salih; Nganga, Rose; Thomas, Raquela J; Oleinik, Natalia; Baron, Kyla D; Szulc, Zdzislaw M; Ruvolo, Peter; Kornblau, Steven; Andreeff, Michael; Ogretmen, Besim

    2016-10-13

    Signaling pathways regulated by mutant Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD), which mediate resistance to acute myeloid leukemia (AML) cell death, are poorly understood. Here, we reveal that pro-cell death lipid ceramide generation is suppressed by FLT3-ITD signaling. Molecular or pharmacologic inhibition of FLT3-ITD reactivated ceramide synthesis, selectively inducing mitophagy and AML cell death. Mechanistically, FLT3-ITD targeting induced ceramide accumulation on the outer mitochondrial membrane, which then directly bound autophagy-inducing light chain 3 (LC3), involving its I35 and F52 residues, to recruit autophagosomes for execution of lethal mitophagy. Short hairpin RNA (shRNA)-mediated knockdown of LC3 prevented AML cell death in response to FLT3-ITD inhibition by crenolanib, which was restored by wild-type (WT)-LC3, but not mutants of LC3 with altered ceramide binding (I35A-LC3 or F52A-LC3). Mitochondrial ceramide accumulation and lethal mitophagy induction in response to FLT3-ITD targeting was mediated by dynamin-related protein 1 (Drp1) activation via inhibition of protein kinase A-regulated S637 phosphorylation, resulting in mitochondrial fission. Inhibition of Drp1 prevented ceramide-dependent lethal mitophagy, and reconstitution of WT-Drp1 or phospho-null S637A-Drp1 but not its inactive phospho-mimic mutant (S637D-Drp1), restored mitochondrial fission and mitophagy in response to crenolanib in FLT3-ITD(+) AML cells expressing stable shRNA against endogenous Drp1. Moreover, activating FLT3-ITD signaling in crenolanib-resistant AML cells suppressed ceramide-dependent mitophagy and prevented cell death. FLT3-ITD(+) AML drug resistance is attenuated by LCL-461, a mitochondria-targeted ceramide analog drug, in vivo, which also induced lethal mitophagy in human AML blasts with clinically relevant FLT3 mutations. Thus, these data reveal a novel mechanism which regulates AML cell death by ceramide-dependent mitophagy in response

  14. Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial.

    PubMed

    Schweitzer, Jana; Zimmermann, Martin; Rasche, Mareike; von Neuhoff, Christine; Creutzig, Ursula; Dworzak, Michael; Reinhardt, Dirk; Klusmann, Jan-Henning

    2015-08-01

    Despite recent advances in the treatment of children with acute megakaryoblastic leukemia (AMKL) using intensified treatment protocols, clear prognostic indicators, and treatment recommendations for this acute myeloid leukemia (AML) subgroup are yet to be defined. Here, we report the outcome of 97 pediatric patients with de novo AMKL (excluding Down syndrome [DS]) enrolled in the prospective multicenter studies AML-BFM 98 and AML-BFM 04 (1998-2014). AMKL occurred in 7.4 % of pediatric AML cases, at younger age (median 1.44 years) and with lower white blood cell count (mean 16.5 × 10(9)/L) as compared to other AML subgroups. With 60 ± 5 %, children with AMKL had a lower 5-year overall survival (5-year OS; vs. 68 ± 1 %, P log rank = 0.038). Yet, we achieved an improved 5-year OS in AML-BFM 04 compared to AML-BFM 98 (70 ± 6 % vs. 45 ± 8 %, P log rank = 0.041). Allogeneic hematopoietic stem cell transplantation in first remission did not provide a significant survival benefit (5-year OS 70 ± 11 % vs. 63 ± 6 %; P Mantel-Byar = 0.85). Cytogenetic data were available for n = 78 patients. AMKL patients with gain of chromosome 21 had a superior 5-year OS (80 ± 9 %, P log rank = 0.034), whereas translocation t(1;22)(p13;q13) was associated with an inferior 5-year event-free survival (38 ± 17 %, P log rank = 0.04). However, multivariate analysis showed that treatment response (bone marrow morphology on day 15 and 28) was the only independent prognostic marker (RR = 4.39; 95 % CI, 1.97-9.78). Interestingly, GATA1-mutations were detected in six patients (11 %) without previously known trisomy 21. Thus, AMKL (excluding DS) remains an AML subgroup with inferior outcome. Nevertheless, with intensive therapy regimens, a steep increase in the survival rates was achieved.

  15. The promoter of miR-663 is hypermethylated in Chinese pediatric acute myeloid leukemia (AML)

    PubMed Central

    2013-01-01

    Background There is growing evidence supporting a role for microRNAs (miRNA) as targets in aberrant mechanisms of DNA hypermethylation. Epigenetic silencing of tumor suppressor miRNAs, including miR-663, which has recently been reported to be inactivated by hypermethylation in several cancers, may play important roles in pediatric acute myeloid leukemia (AML). However, expression of miR-663 and its promoter methylation remain status unclear in childhood leukemia. Methods Promoter methylation status of miR-663 was investigated by methylation specific PCR (MSP) and bisulfate genomic sequencing (BGS). Transcriptional expression of miR-663 was evaluated by semi-quantitative and real-time PCR, and the relationship between expression of miR-663 and promoter methylation was confirmed using 5-aza-2’-deoxycytidine (5-Aza) demethylation reagent. Results MiR-663 was aberrantly methylated in 45.5% (5/11) leukemia cell lines; BGS showed that the promoter was significantly methylated in three AML cell lines; methylation of miR-663 was significantly higher in Chinese pediatric AML patients [41.4% (29/70)] compared to normal bone marrow (NBM) control samples [10.0% (3/30)]. These results were confirmed by both BGS and 5-Aza demethylation analysis. In addition, miR-663 transcript expression was significantly lower in AML patients, both with and without miR-663 methylation, compared to controls; however, there were no significant differences in clinical features or French-American-British (FAB) classification between patients with and without miR-663 methylation. Conclusions Expression of miR-663 was significantly lower in pediatric AML cells compared to NBM controls; furthermore, a high frequency of miR-663 promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Inactivation of miR-663 by promoter hypermethylation could be affected by 5-Aza demethylation. These findings suggest that hypermethylation of the miR-663 promoter may be an early event in

  16. ELMO1 Is Upregulated in AML CD34+ Stem/Progenitor Cells, Mediates Chemotaxis and Predicts Poor Prognosis in Normal Karyotype AML

    PubMed Central

    Capala, Marta E.; Vellenga, Edo; Schuringa, Jan Jacob

    2014-01-01

    Both normal as well leukemic hematopoietic stem cells critically depend on their microenvironment in the bone marrow for processes such as self-renewal, survival and differentiation, although the exact pathways that are involved remain poorly understood. We performed transcriptome analysis on primitive CD34+ acute myeloid leukemia (AML) cells (n = 46), their more differentiated CD34− leukemic progeny, and normal CD34+ bone marrow cells (n = 31) and focused on differentially expressed genes involved in adhesion and migration. Thus, Engulfment and Motility protein 1 (ELMO1) was identified amongst the top 50 most differentially expressed genes. ELMO1 is a crucial link in the signaling cascade that leads to activation of RAC GTPases and cytoskeleton rearrangements. We confirmed increased ELMO1 expression at the mRNA and protein level in a panel of AML samples and showed that high ELMO1 expression is an independent negative prognostic factor in normal karyotype (NK) AML in three large independent patient cohorts. Downmodulation of ELMO1 in human CB CD34+ cells did not significantly alter expansion, progenitor frequency or differentiation in stromal co-cultures, but did result in a decreased frequency of stem cells in LTC-IC assays. In BCR-ABL-transduced human CB CD34+ cells depletion of ELMO1 resulted in a mild decrease in proliferation, but replating capacity of progenitors was severely impaired. Downregulation of ELMO1 in a panel of primary CD34+ AML cells also resulted in reduced long-term growth in stromal co-cultures in two out of three cases. Pharmacological inhibition of the ELMO1 downstream target RAC resulted in a severely impaired proliferation and survival of leukemic cells. Finally, ELMO1 depletion caused a marked decrease in SDF1-induced chemotaxis of leukemic cells. Taken together, these data show that inhibiting the ELMO1-RAC axis might be an alternative way to target leukemic cells. PMID:25360637

  17. Unfälle mit motorisierten Zweirädern

    NASA Astrophysics Data System (ADS)

    Tschirschwitz, Christian

    Der Fahrer eines Pkw Opel Astra überquerte mit seinem Pkw von einer untergeordneten Einmündung kommend eine außerörtliche Bundesstraße in gerade Richtung. Dabei kam es zur Kollision mit einem sich von rechts vorfahrtsberechtigt annähernden Krad Suzuki RGV250. Der Anprall des Krades erfolgte mit dem Heck an die rechte Pkw-Flanke zwischen vorderem Radausschnitt und Fahrzeugecke. Der Krad-Fahrer, welcher sofort tot war und das Zweirad verklemmten sich am Pkw und verblieben relativ zu selbigem annähernd in Kollisionsstellung.

  18. Final Technical Report for the MIT Annular Fuel Research Project

    SciTech Connect

    Mujid S. Kazimi; Pavel Hejzlar

    2008-01-31

    MIT-NFC-PR-082 (January 2006) Abstract This summary provides an overview of the results of the U.S. DOE funded NERI (Nuclear Research ENergy Initiative) program on development of the internally and externally cooled annular fuel for high power density PWRs. This new fuel was proposed by MIT to allow a substantial increase in poer density (on the order of 30% or higher) while maintaining or improving safety margins. A comprehensive study was performed by a team consisting of MIT (lead organization), Westinghuse Electric Corporation, Gamma Engineering Corporation, Framatome ANP(formerly Duke Engineering) and Atomic Energy of Canada Limited.

  19. NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML

    PubMed Central

    Bar-Natan, Michal; Haibe-Kains, Benjamin; Pilarski, Patrick M.; Bach, Christian; Pevzner, Samuel; Calimeri, Teresa; Avet-Loiseau, Herve; Lode, Laurence; Verselis, Sigitas; Fox, Edward A.; Galinsky, Ilene; Mathews, Steven; Dagogo-Jack, Ibiayi; Wadleigh, Martha; Steensma, David P.; Motyckova, Gabriela; Deangelo, Daniel J.; Quackenbush, John; Tenen, Daniel G.; Stone, Richard M.; Griffin, James D.

    2014-01-01

    Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34+ bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics. PMID:24574459

  20. [Reversed effect of valproic acid on transcription inhibition of AML1-ETO fusion protein of kasumi-1 leukemic cell line].

    PubMed

    Zhao, Lei; Zhu, Cui-Min; Zhang, Zhi-Hua; Tian, Wen-Liang; Hao, Chang-Lai

    2009-04-01

    This study was aimed to investigate the mechanism of histone deacetylase (HDAC) inhibitor, valproic acid (VPA), reversing transcription inhibition of AML1-ETO fusion protein in Kasumi-1 cell line. The mRNA expressions of AML1-ETO, AML1 and cyclin D2 were detected by semi-quantitation RT-PCR after treating kasumi-1 cells with VPA at different doses/and different time points. The results indicated that the mRNA expression of AML1-ETO showed no obvious change, when kasumi-1 cells were treated with VPA. Compared with control group, the expression level of AML1 mRNA significantly increased in a dose-dependent manner. Compared with control group, the expression level of cyclin D2 mRNA significantly decreased when kasumi-1 cells had been treated with 3 mmol/L VPA as well as kasumi-1 cells were treated with different concentrations of VPA for 3 days. In conclusion, VPA could remove transcription inhibition of AML1-ETO fusion protein, increase transcription of AML1 and down-regulate mRNA expression of AML1 target gene cyclin D2 through HDAC inhibiting activity.

  1. 30 CFR 872.20 - What will OSM do with unappropriated AML funds currently allocated to the Rural Abandoned Mine...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 3 2012-07-01 2012-07-01 false What will OSM do with unappropriated AML funds... MONEYS AVAILABLE TO ELIGIBLE STATES AND INDIAN TRIBES § 872.20 What will OSM do with unappropriated AML... will make available any moneys that remain allocated to RAMP and that were not appropriated or moved...

  2. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice

    PubMed Central

    Schessl, Christina; Rawat, Vijay P.S.; Cusan, Monica; Deshpande, Aniruddha; Kohl, Tobias M.; Rosten, Patricia M.; Spiekermann, Karsten; Humphries, R. Keith; Schnittger, Susanne; Kern, Wolfgang; Hiddemann, Wolfgang; Quintanilla-Martinez, Leticia; Bohlander, Stefan K.; Feuring-Buske, Michaela; Buske, Christian

    2005-01-01

    The molecular characterization of leukemia has demonstrated that genetic alterations in the leukemic clone frequently fall into 2 classes, those affecting transcription factors (e.g., AML1-ETO) and mutations affecting genes involved in signal transduction (e.g., activating mutations of FLT3 and KIT). This finding has favored a model of leukemogenesis in which the collaboration of these 2 classes of genetic alterations is necessary for the malignant transformation of hematopoietic progenitor cells. The model is supported by experimental data indicating that AML1-ETO and FLT3 length mutation (FLT3-LM), 2 of the most frequent genetic alterations in AML, are both insufficient on their own to cause leukemia in animal models. Here we report that AML1-ETO collaborates with FLT3-LM in inducing acute leukemia in a murine BM transplantation model. Moreover, in a series of 135 patients with AML1-ETO–positive AML, the most frequently identified class of additional mutations affected genes involved in signal transduction pathways including FLT3-LM or mutations of KIT and NRAS. These data support the concept of oncogenic cooperation between AML1-ETO and a class of activating mutations, recurrently found in patients with t(8;21), and provide a rationale for therapies targeting signal transduction pathways in AML1-ETO–positive leukemias. PMID:16025155

  3. Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS

    PubMed Central

    Barreyro, Laura; Will, Britta; Bartholdy, Boris; Zhou, Li; Todorova, Tihomira I.; Stanley, Robert F.; Ben-Neriah, Susana; Montagna, Cristina; Parekh, Samir; Pellagatti, Andrea; Boultwood, Jacqueline; Paietta, Elisabeth; Ketterling, Rhett P.; Cripe, Larry; Fernandez, Hugo F.; Greenberg, Peter L.; Tallman, Martin S.; Steidl, Christian; Mitsiades, Constantine S.; Verma, Amit

    2012-01-01

    Cellular and interpatient heterogeneity and the involvement of different stem and progenitor compartments in leukemogenesis are challenges for the identification of common pathways contributing to the initiation and maintenance of acute myeloid leukemia (AML). Here we used a strategy of parallel transcriptional analysis of phenotypic long-term hematopoietic stem cells (HSCs), short-term HSCs, and granulocyte-monocyte progenitors from individuals with high-risk (−7/7q−) AML and compared them with the corresponding cell populations from healthy controls. This analysis revealed dysregulated expression of 11 genes, including IL-1 receptor accessory protein (IL1RAP), in all leukemic stem and progenitor cell compartments. IL1RAP protein was found to be overexpressed on the surface of HSCs of AML patients, and marked cells with the −7/7q− anomaly. IL1RAP was also overexpressed on HSCs of patients with normal karyotype AML and high-risk myelodysplastic syndrome, suggesting a pervasive role in different disease subtypes. High IL1RAP expression was independently associated with poor overall survival in 3 independent cohorts of AML patients (P = 2.2 × 10−7). Knockdown of IL1RAP decreased clonogenicity and increased cell death of AML cells. Our study identified genes dysregulated in stem and progenitor cells in −7/7q− AML, and suggests that IL1RAP may be a promising therapeutic and prognostic target in AML and high-risk myelodysplastic syndrome. PMID:22723552

  4. Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS.

    PubMed

    Barreyro, Laura; Will, Britta; Bartholdy, Boris; Zhou, Li; Todorova, Tihomira I; Stanley, Robert F; Ben-Neriah, Susana; Montagna, Cristina; Parekh, Samir; Pellagatti, Andrea; Boultwood, Jacqueline; Paietta, Elisabeth; Ketterling, Rhett P; Cripe, Larry; Fernandez, Hugo F; Greenberg, Peter L; Tallman, Martin S; Steidl, Christian; Mitsiades, Constantine S; Verma, Amit; Steidl, Ulrich

    2012-08-09

    Cellular and interpatient heterogeneity and the involvement of different stem and progenitor compartments in leukemogenesis are challenges for the identification of common pathways contributing to the initiation and maintenance of acute myeloid leukemia (AML). Here we used a strategy of parallel transcriptional analysis of phenotypic long-term hematopoietic stem cells (HSCs), short-term HSCs, and granulocyte-monocyte progenitors from individuals with high-risk (-7/7q-) AML and compared them with the corresponding cell populations from healthy controls. This analysis revealed dysregulated expression of 11 genes, including IL-1 receptor accessory protein (IL1RAP), in all leukemic stem and progenitor cell compartments. IL1RAP protein was found to be overexpressed on the surface of HSCs of AML patients, and marked cells with the -7/7q- anomaly. IL1RAP was also overexpressed on HSCs of patients with normal karyotype AML and high-risk myelodysplastic syndrome, suggesting a pervasive role in different disease subtypes. High IL1RAP expression was independently associated with poor overall survival in 3 independent cohorts of AML patients (P = 2.2 × 10(-7)). Knockdown of IL1RAP decreased clonogenicity and increased cell death of AML cells. Our study identified genes dysregulated in stem and progenitor cells in -7/7q- AML, and suggests that IL1RAP may be a promising therapeutic and prognostic target in AML and high-risk myelodysplastic syndrome.

  5. Phase I Trial of the Selective Inhibitor of Nuclear Export, KPT-330, in Relapsed Childhood ALL and AML

    ClinicalTrials.gov

    2017-08-21

    Relapsed Acute Lymphoblastic Leukemia (ALL); Refractory Acute Lymphoblastic Leukemia (ALL); Relapsed Acute Myelogenous Leukemia (AML); Refractory Acute Myelogenous Leukemia (AML); Relapsed Mixed Lineage Leukemia; Refractory Mixed Lineage Leukemia; Relapsed Biphenotypic Leukemia; Refractory Biphenotypic Leukemia; Chronic Myelogenous Leukemia (CML) in Blast Crisis

  6. Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.

    PubMed

    Morgado-Palacin, Isabel; Day, Amanda; Murga, Matilde; Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua-Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J; Hubbard, Chad; Armstrong, Scott A; Nussenzweig, André; Fernandez-Capetillo, Oscar

    2016-09-13

    Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.

  7. ABCB1-Gen-Polymorphismus in einer polnischen Kohorte ist mit Risiko für bullöses Pemphigoid assoziiert.

    PubMed

    Rychlik-Sych, Mariola; Barańska, Małgorzata; Dudarewicz, Michał; Skrętkowicz, Jadwiga; Żebrowska, Agnieszka; Owczarek, Jacek; Waszczykowska, Elżbieta

    2017-05-01

    Polymorphismen im ABCB1-Gen, das für das P-Glykoprotein kodiert, können die intrazelluläre Konzentration von Xenobiotika beeinflussen und so zur Entwicklung von Autoimmunerkrankungen, einschließlich des bullösen Pemphigoids (BP), beitragen. In der vorliegenden Studie sollte untersucht werden, ob in einer polnischen Kohorte die C3435T- und G2677T/A-Polymorphismen im ABCB1-Gen mit dem Risiko für ein BP assoziiert sind. Die Studie umfasste 71 Patienten mit BP und 156 gesunde Probanden. Der C3435T-Polymorphismus wurde mittels PCR-RFLP bestimmt und der G2677T/A-Polymorphismus mittels Allel-spezifischer PCR. Es gab zwar keine Korrelation zwischen dem C3435-Polymorphismus und dem BP-Risiko, aber wir konnten eine derartige Assoziation hinsichtlich des G2677T/A-Polymorphismus nachweisen. Das relative Risiko eines BP war bei Personen mit dem 2677TA-Genotyp um mehr als den Faktor fünf erhöht (OR = 5,52; p = 0,0063) und bei Trägern des 2677TT-Genotyps mehr als verdoppelt (OR = 2,40; p = 0,0076). Mit 2,40 (p = 0,000018) war die OR bei Trägern des 2677T-Allels ebenfalls erhöht. Die höhere Prävalenz des 2677GG-Genotyps und des 2677G-Allels bei der Kontrollgruppe sowie eine OR < 1,0 (0,22 beziehungsweise 0,33) legen eine Schutzfunktion des 2677G-Allels hinsichtlich der Ausbildung eines BP nahe. Die Ergebnisse der vorliegenden Studie zeigen, dass der G2677T/A-Polymorphismus im ABCB1-Gen das Risiko für die Entstehung eines BP beeinflussen könnte. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  8. Identification of ins(8;21) with AML1/ETO fusion in acute myelogenous leukemia M2 by molecular cytogenetics.

    PubMed

    Urioste, M; Martínez-Ramírez, A; Cigudosa, J C; Mateo, M S; Martínez, P; Contra, T; Benítez, J

    2002-02-01

    A high percentage of cases of acute myelogenous leukemia (AML) of the M2 subtype show a rearrangement between the AML1 and ETO genes. The detection of the AML1/ETO fusion has clinical relevance because patients with this subtype have a good prognosis. We present the results of conventional and molecular cytogenetic studies in a patient with acute myelogenous leukemia French-American-British M2 classification, who had a complex karyotype involving chromosomes 8 and 21. Dual-color fluorescence in situ hybridization (FISH) using the AML1/ETO probe demonstrated a recombination of both genes on an add(8) chromosome. The use of other FISH probes (CEP8, c-myc and TEL21) and spectral karyotyping indicated that AML1/ETO fusion occurred as a consequence of a previously undescribed ins(8;21)(q22;q22.1q22.3).

  9. Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts.

    PubMed

    Vasu, Sumithira; He, Shun; Cheney, Carolyn; Gopalakrishnan, Bhavani; Mani, Rajeswaran; Lozanski, Gerard; Mo, Xiaokui; Groh, Veronica; Whitman, Susan P; Konopitzky, Renate; Kössl, Christian; Bucci, Donna; Lucas, David M; Yu, Jianhua; Caligiuri, Michael A; Blum, William; Adam, Paul J; Borges, Eric; Rueter, Bjoern; Heider, Karl-Heinz; Marcucci, Guido; Muthusamy, Natarajan

    2016-06-09

    Acute myeloid leukemia (AML) is the most common type of acute leukemia, affecting older individuals at a median age of 67 years. Resistance to intensive induction chemotherapy is the major cause of death in elderly AML; hence, novel treatment strategies are warranted. CD33-directed antibody-drug conjugates (gemtuzumab ozogamicin) have been shown to improve overall survival, validating CD33 as a target for antibody-based therapy of AML. Here, we report the in vitro efficacy of BI 836858, a fully human, Fc-engineered, anti-CD33 antibody using AML cell lines and primary AML blasts as targets. BI 836858-opsonized AML cells significantly induced both autologous and allogeneic natural killer (NK)-cell degranulation and NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In vitro treatment of AML blasts with decitabine (DAC) or 5-azacytidine, 2 hypomethylating agents that show efficacy in older patients, did not compromise BI 836858-induced NK-cell-mediated ADCC. Evaluation of BI 836858-mediated ADCC in serial marrow AML aspirates in patients who received a 10-day course of DAC (pre-DAC, days 4, 11, and 28 post-DAC) revealed significantly higher ADCC in samples at day 28 post-DAC when compared with pre-DAC treatment. Analysis of ligands to activating receptors (NKG2D) showed significantly increased NKG2D ligand [NKG2DL] expression in day 28 post-DAC samples compared with pre-DAC samples; when NKG2DL receptor was blocked using antibodies, BI 836858-mediated ADCC was significantly decreased, suggesting that DAC enhances AML blast susceptibility to BI 836858 by upregulating NKG2DL. These data provide a rationale for combination therapy of Fc-engineered antibodies such as BI 836858 with azanucleosides in elderly patients with AML.

  10. Decitabine enhances anti-CD33 monoclonal antibody BI 836858–mediated natural killer ADCC against AML blasts

    PubMed Central

    Vasu, Sumithira; He, Shun; Cheney, Carolyn; Gopalakrishnan, Bhavani; Mani, Rajeswaran; Lozanski, Gerard; Mo, Xiaokui; Groh, Veronica; Whitman, Susan P.; Konopitzky, Renate; Kössl, Christian; Bucci, Donna; Lucas, David M.; Yu, Jianhua; Caligiuri, Michael A.; Blum, William; Adam, Paul J.; Borges, Eric; Rueter, Bjoern; Heider, Karl-Heinz; Marcucci, Guido

    2016-01-01

    Acute myeloid leukemia (AML) is the most common type of acute leukemia, affecting older individuals at a median age of 67 years. Resistance to intensive induction chemotherapy is the major cause of death in elderly AML; hence, novel treatment strategies are warranted. CD33-directed antibody-drug conjugates (gemtuzumab ozogamicin) have been shown to improve overall survival, validating CD33 as a target for antibody-based therapy of AML. Here, we report the in vitro efficacy of BI 836858, a fully human, Fc-engineered, anti-CD33 antibody using AML cell lines and primary AML blasts as targets. BI 836858–opsonized AML cells significantly induced both autologous and allogeneic natural killer (NK)-cell degranulation and NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC). In vitro treatment of AML blasts with decitabine (DAC) or 5-azacytidine, 2 hypomethylating agents that show efficacy in older patients, did not compromise BI 836858–induced NK-cell–mediated ADCC. Evaluation of BI 836858–mediated ADCC in serial marrow AML aspirates in patients who received a 10-day course of DAC (pre-DAC, days 4, 11, and 28 post-DAC) revealed significantly higher ADCC in samples at day 28 post-DAC when compared with pre-DAC treatment. Analysis of ligands to activating receptors (NKG2D) showed significantly increased NKG2D ligand [NKG2DL] expression in day 28 post-DAC samples compared with pre-DAC samples; when NKG2DL receptor was blocked using antibodies, BI 836858–mediated ADCC was significantly decreased, suggesting that DAC enhances AML blast susceptibility to BI 836858 by upregulating NKG2DL. These data provide a rationale for combination therapy of Fc-engineered antibodies such as BI 836858 with azanucleosides in elderly patients with AML. PMID:27013443

  11. Mapping of the gracile axonal dystrophy (gad) gene to a region between D5Mit197 and D5Mit113 on proximal mouse chromosome 5

    SciTech Connect

    Suh, J.G.; Yamanishi, T.; Matsui, K.

    1995-06-10

    The gracile axonal dystrophy (gad) mouse, which shows hereditary sensory ataxia and motor paresis, has been morphologically characterized by the dying back type of axonal degeneration in the nerve terminals of dorsal root ganglion cells and motor neurons. In the present study, using an intraspecific backcross between gad and C57BL/6J mice, the gracile axonal dystrophy (gad) gene was mapped to a region between D5Mit197 and D5Mit113. Estimated distances between gad and D5Mit197 and between gad and D5Mit113 are 0.4 {plus_minus} 0.3 and 5.0 {plus_minus} 1.0 cM, respectively. The gene order was defined: centromere-D5Mit81-D5Mit233-D5Mit184/D5Mit254-D5Mit256-D5Mit197-gad-D5Mit113-D5Mit7. The mouse map location of the gad locus appears to be in a region homologous to human 4p15-p16. Our present data suggest that the nearest flanking marker D5Mit197 provides a useful anchor for the isolation of the gad gene in a yeast artificial chromosome contig. 19 refs., 2 figs.

  12. Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia.

    PubMed

    Harada, Hironori; Harada, Yuka; Tanaka, Hideo; Kimura, Akiro; Inaba, Toshiya

    2003-01-15

    Somatically acquired point mutations of AML1/RUNX1 gene have been recently identified in rare cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Moreover, germ line mutations of AML1 were found in an autosomal dominant disease, familial platelet disorder with predisposition to AML (FPD/AML), suggesting that AML1 mutants, as well as AML1 chimeras, contribute to the transformation of hematopoietic progenitors. In this report, we showed that AML1 point mutations were found in 6 (46%) of 13 MDS patients among atomic bomb (A-bomb) survivors in Hiroshima. Unlike acute or chronic leukemia patients among A-bomb survivors, MDS patients exposed relatively low-dose radiation and developed the disease after a long latency period. AML1 mutations also were found in 5 (38%) of 13 therapy-related AML/MDS patients who were treated with alkylating agents with or without local radiation therapy. In contrast, frequency of AML1 mutation in sporadic MDS patients was 2.7% (2 of 74). Among AML1 mutations identified in this study, truncated-type mutants lost DNA binding potential and trans-activation activity. All missense mutations with one exception (Gly42Arg) lacked DNA binding ability and down-regulated the trans-activation potential of wild-type AML1 in a dominant-negative fashion. The Gly42Arg mutation that was shared by 2 patients bound DNA even more avidly than wild-type AML1 and enhanced the trans-activation potential of normal AML1. These results suggest that AML1 point mutations are related to low-dose radiation or alkylating agents and play a role distinct from that of leukemogenic chimeras as a result of chromosomal translocations caused by sublethal radiation or topoisomerase II inhibitors.

  13. MIT ASTROMAG 1.7 meter disk magnet design report

    NASA Technical Reports Server (NTRS)

    Marston, P. G.; Hale, J. R.; Vieira, R.; Zhukovsky, A.; Titus, P. H.; Sullivan, J. D.; Dawson, A. M.

    1990-01-01

    MIT has proposed a magnet design for ASTROMAG, which has demonstrated substantial improvement in performance as compared with the present HEAO baseline design. Several advantages of the MIT disk design are listed along with design characteristics. Details of field contours and active field regions are shown along with comparisons with other designs. Three alternative design configurations for the ASTROMAG disk coils are summarized. The parameters of the conductors are listed and basic parameters for each of the complete systems are shown.

  14. Negative immunomagnetic selection of T cells from peripheral blood of presentation AML specimens.

    PubMed

    Le Dieu, Rifca; Taussig, David; Lister, T Andrew; Gribben, John G

    2009-08-31

    To date, studies on T cells in acute myeloid leukemia (AML) have been limited to flow cytometric analysis of whole peripheral blood mononuclear cell (PBMC) specimens or functional work looking at the impact of AML myeloblasts on normal or remission T cells. This lack of information on T cells at the time of presentation with disease is due in part to the difficulty in isolating sufficiently pure T cells from these specimens for further study. Negative immunomagnetic selection has been the method of choice for isolating immune cells for functional studies due to concerns that binding antibodies to the cell surface may induce cellular activation, block ligand-receptor interactions or result in immune clearance. In order specifically to study T cells in presentation AML specimens, we set out to develop a method of isolating highly pure CD4 and CD8 T cells by negative selection from the peripheral blood (PB) of newly diagnosed AML patients. This technique, unlike T cell selection from PB from normal individuals or from patients with chronic lymphocytic leukaemia, was extremely problematic due to properties of the leukaemic myeloblasts. A successful method was eventually optimized requiring the use of a custom antibody cocktail consisting of CD33, CD34, CD123, CD11c and CD36, to deplete myeloblasts.

  15. Improved FLT3/ITD PCR assay predicts outcome following allogeneic transplant for AML

    PubMed Central

    Grunwald, Michael R.; Tseng, Li-Hui; Lin, Ming-Tseh; Pratz, Keith W.; Eshleman, James R.; Levis, Mark J.; Gocke, Christopher D.

    2014-01-01

    Acute myeloid leukemia (AML) patients harboring internal tandem duplication (ITD) mutations of the FMS-like tyrosine kinase 3 (FLT3) gene carry a poor prognosis. While allogeneic transplantation may improve outcomes, relapse occurs frequently. The FLT3/ITD mutation has been deemed an unsuitable minimal residual disease (MRD) marker because it is unstable and because the standard assay for the mutation is relatively insensitive. The FLT3 mutation is undetectable by polymerase chain reaction (PCR) at pre- or post-transplant time points in many FLT3/ITD AML patients who subsequently relapse following transplant. We report the application of a new technique, tandem duplication PCR (TD-PCR), for detecting MRD in FLT3/ITD AML patients. Between October 2004 and January 2012, 54 FLT3/ITD AML patients in remission underwent transplantation at our institution. Of 37 patients with available Day 60 marrow samples, 28 (76%) were evaluable for MRD detection. In seven (25%) of the 28 patients, the FLT3/ITD mutation was detectable by TD-PCR, but not by standard PCR, on day 60. Six out of the seven patients (86%) with MRD by TD-PCR have relapsed to date compared with only 2 of 21 (10%) patients who were negative for MRD (p = 0.0003). The ability to detect MRD by this sensitive technique may provide an opportunity for early clinical intervention. PMID:25240816

  16. Selective killing of candidate AML stem cells by antibody targeting of IL1RAP.

    PubMed

    Askmyr, Maria; Ågerstam, Helena; Hansen, Nils; Gordon, Sandra; Arvanitakis, Alexandros; Rissler, Marianne; Juliusson, Gunnar; Richter, Johan; Järås, Marcus; Fioretos, Thoas

    2013-05-02

    IL1RAP, a co-receptor for interleukin (IL)-1 and IL-33 receptors, was previously found to be highly upregulated on candidate chronic myeloid leukemia stem cells, allowing for leukemia-selective killing using IL1RAP-targeting antibodies. We analyzed IL1RAP expression in a consecutive series of 29 patients with acute myeloid leukemia (AML) and, based on the level of expression in mononuclear cells (MNCs), we divided the samples into 3 groups: IL1RAP low (n = 6), IL1RAP intermediate (n = 11), and IL1RAP high (n = 12). Within the CD34+CD38- population, the intermediate and high groups expressed higher levels of IL1RAP than did corresponding normal cells. With the aim to target AML stem cells, an anti-IL1RAP monoclonal antibody was generated followed by isotype switching for improved antibody-dependent, cell-mediated cytotoxicity activity. Using this antibody, we achieved selective killing of AML MNC, CD34+CD38+, and CD34+CD38- cells. Our findings demonstrate that IL1RAP is a promising new therapeutic target in AML.

  17. Histological and immunohistochemical features of gingival enlargement in a patient with AML.

    PubMed

    Sonoi, Norihiro; Soga, Yoshihiko; Maeda, Hiroshi; Ichimura, Koichi; Yoshino, Tadashi; Aoyama, Kazutoshi; Fujii, Nobuharu; Maeda, Yoshinobu; Tanimoto, Mitsune; Logan, Richard; Raber-Durlacher, Judith; Takashiba, Shogo

    2012-07-01

    Here, we discuss the pathophysiology of leukemia-associated gingival enlargement based on a case of acute myelomonocytic leukemia (AML-M4) with typical gingival enlargement. Uniquely, this patient was well enough to allow full periodontal examination and incisional gingival biopsy to be performed both before and after chemotherapy. The patient was a 39-year-old Japanese woman with AML-M4 showing gingival enlargement. Histological and immunohistochemical features of gingiva and bacterial counts in the periodontal pockets were examined before and after chemotherapy. The results were as follows: (1) infiltration of myelomonocytic blasts in enlarged gingiva; (2) resolution of gingival enlargement with complete remission of AML by anticancer chemotherapy; and (3) the numbers of bacteria in the periodontal pockets were not high and were not altered before or after chemotherapy. In patients with AML-M4, remarkable mucosal enlargement is not generally observed in the body except in the gingiva. We hypothesized that antigens derived from periodontal bacteria, even if they are not present in large numbers, could act as chemoattractants for myelomonocytic leukemic cells.

  18. Budget impact analysis of CYP2C19-guided voriconazole prophylaxis in AML

    PubMed Central

    Mason, Neil T.; Bell, Gillian C.; Quilitz, Rod E.; Greene, John N.; McLeod, Howard L.

    2015-01-01

    Objectives The objective of this study was to determine the economic impact of proactive, CYP2C19 genotype-guided voriconazole prophylaxis in AML. Methods An Excel-based model was created to project the cost of treating a simulated cohort of severely neutropenic AML patients undergoing antifungal prophylaxis. The model compares (i) standard prophylactic dosing with voriconazole and (ii) CYP2C19 genotyping of all AML patients to guide voriconazole dosing and prescribing. Results Based on the model, genotype-guided dosing of voriconazole conservatively spares 2.3 patients per year from invasive fungal infections. Implementing proactive genotyping of all AML patients in a simulated 100 patient cohort is expected to save a total of $41467 or $415 per patient. Conclusions The model, based on the robust literature of clinical and economic data, predicts that proactive genotype-guided voriconazole prophylaxis is likely to yield modest cost savings while improving patient outcomes. The primary driver of savings is the avoidance of expensive antifungal treatment and extended hospital stays, costing $30 952 per patient, in patients succumbing to fungal infection. PMID:26233624

  19. Investigational BET bromodomain protein inhibitors in early stage clinical trials for acute myelogenous leukemia (AML).

    PubMed

    Braun, Thorsten; Gardin, Claude

    2017-07-01

    Acute myelogenous leukemia (AML) is a heterogeneous group of malignancies driven by genetic mutations and deregulated epigenetic control. Relapse/refractory disease remains frequent in younger patients and even more so in older patients, including treatment with epigenetic drugs in this age group, mainly with hypomethylating agents. New treatment strategies are urgently needed. The recent discovery that epigenetic readers of the bromodomain (BRD) and extraterminal (BET) protein family, are crucial for AML maintenance by transcription of oncogenic c-MYC lead to rapid development of BET inhibitors entering clinical trials. Areas covered: We provide a critical overview using main sources for the use of BET inhibitors in AML treatment. Limits of this treatment approach including resistance mechanisms and future directions including development of new generation BET inhibitors and combination strategies with other drugs are detailed. Expert opinion: BET inhibitors were expected to overcome limits of conventional treatment in patients as impressive in vitro data emerged recently in well-characterized AML subsets, including those associated with poor risk characteristics in the clinic. Nevertheless single activity of BET inhibitors appears to be modest and resistance mechanisms were already identified. BET inhibitors with alternative mechanisms of action and/or combination strategies with epigenetic drugs should be tested.

  20. A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo.

    PubMed

    Saito, Yoriko; Yuki, Hitomi; Kuratani, Mitsuo; Hashizume, Yoshinobu; Takagi, Shinsuke; Honma, Teruki; Tanaka, Akiko; Shirouzu, Mikako; Mikuni, Junko; Handa, Noriko; Ogahara, Ikuko; Sone, Akiko; Najima, Yuho; Tomabechi, Yuri; Wakiyama, Motoaki; Uchida, Naoyuki; Tomizawa-Murasawa, Mariko; Kaneko, Akiko; Tanaka, Satoshi; Suzuki, Nahoko; Kajita, Hiroshi; Aoki, Yuki; Ohara, Osamu; Shultz, Leonard D; Fukami, Takehiro; Goto, Toshio; Taniguchi, Shuichi; Yokoyama, Shigeyuki; Ishikawa, Fumihiko

    2013-04-17

    Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to contribute to disease relapse, leading to poor long-term outcomes for patients with acute myeloid leukemia (AML). We previously identified a Src-family kinase (SFK) member, hematopoietic cell kinase (HCK), as a molecular target that is highly differentially expressed in human primary LSCs compared with human normal hematopoietic stem cells (HSCs). We performed a large-scale chemical library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymatic IC50 (half maximal inhibitory concentration) in the subnanomolar range. A crystal structure revealed that RK-20449 bound the activation pocket of HCK. In vivo administration of RK-20449 to nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/IL2rg(null) mice engrafted with highly aggressive therapy-resistant AML significantly reduced human LSC and non-stem AML burden. By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse and lead to improved patient outcomes in AML.

  1. A Crowdsourcing Approach to Developing and Assessing Prediction Algorithms for AML Prognosis.

    PubMed

    Noren, David P; Long, Byron L; Norel, Raquel; Rrhissorrakrai, Kahn; Hess, Kenneth; Hu, Chenyue Wendy; Bisberg, Alex J; Schultz, Andre; Engquist, Erik; Liu, Li; Lin, Xihui; Chen, Gregory M; Xie, Honglei; Hunter, Geoffrey A M; Boutros, Paul C; Stepanov, Oleg; Norman, Thea; Friend, Stephen H; Stolovitzky, Gustavo; Kornblau, Steven; Qutub, Amina A

    2016-06-01

    Acute Myeloid Leukemia (AML) is a fatal hematological cancer. The genetic abnormalities underlying AML are extremely heterogeneous among patients, making prognosis and treatment selection very difficult. While clinical proteomics data has the potential to improve prognosis accuracy, thus far, the quantitative means to do so have yet to be developed. Here we report the results and insights gained from the DREAM 9 Acute Myeloid Prediction Outcome Prediction Challenge (AML-OPC), a crowdsourcing effort designed to promote the development of quantitative methods for AML prognosis prediction. We identify the most accurate and robust models in predicting patient response to therapy, remission duration, and overall survival. We further investigate patient response to therapy, a clinically actionable prediction, and find that patients that are classified as resistant to therapy are harder to predict than responsive patients across the 31 models submitted to the challenge. The top two performing models, which held a high sensitivity to these patients, substantially utilized the proteomics data to make predictions. Using these models, we also identify which signaling proteins were useful in predicting patient therapeutic response.

  2. Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia

    PubMed Central

    Ford, Anthony M.; Bennett, Caroline A.; Price, Cathy M.; Bruin, M. C. A.; Van Wering, Elisabeth R.; Greaves, Mel

    1998-01-01

    The TEL (ETV6)−AML1 (CBFA2) gene fusion is the most common reciprocal chromosomal rearrangement in childhood cancer occurring in ≈25% of the most predominant subtype of leukemia— common acute lymphoblastic leukemia. The TEL-AML1 genomic sequence has been characterized in a pair of monozygotic twins diagnosed at ages 3 years, 6 months and 4 years, 10 months with common acute lymphoblastic leukemia. The twin leukemic DNA shared the same unique (or clonotypic) but nonconstitutive TEL-AML1 fusion sequence. The most plausible explanation for this finding is a single cell origin of the TEL-AML fusion in one fetus in utero, probably as a leukemia-initiating mutation, followed by intraplacental metastasis of clonal progeny to the other twin. Clonal identity is further supported by the finding that the leukemic cells in the two twins shared an identical rearranged IGH allele. These data have implications for the etiology and natural history of childhood leukemia. PMID:9539781

  3. Activity of 8F4, a T cell receptor-like anti-PR1/HLA-A2 antibody, against primary human AML in vivo

    PubMed Central

    Sergeeva, Anna; He, Hong; Ruisaard, Kathryn; St. John, Lisa; Alatrash, Gheath; Clise-Dwyer, Karen; Li, Dan; Patenia, Rebecca; Hong, Richard; Sukhumalchandra, Pariya; You, M. James; Gagea, Mihai; Ma, Qing; Molldrem, Jeffrey J.

    2016-01-01

    The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a high affinity T cell receptor-like murine monoclonal antibody, 8F4, which binds to the PR1/HLA-A2 complex, mediates lysis of AML, and inhibits leukemia colony formation. Here, we explored whether 8F4 was active in vivo against chemotherapy-resistant AML, including secondary AML. In a screening model, co-incubation of AML with 8F4 ex vivo prevented engraftment of all tested AML subtypes in immunodeficient NSG mice. In a treatment model of established human AML, administration of 8F4 significantly reduced or eliminated AML xenografts and extended survival compared with isotype antibody-treated mice. Moreover, in secondary transfer experiments, mice inoculated with bone marrow from 8F4-treated mice showed no evidence of AML engraftment, supporting possible activity of 8F4 against the subset of AML with self-renewing potential. Our data provide evidence that 8F4 antibody is highly active in AML, including chemotherapy-resistant disease, supporting its potential use as a therapeutic agent in patients with AML. PMID:27055866

  4. Activity of 8F4, a T-cell receptor-like anti-PR1/HLA-A2 antibody, against primary human AML in vivo.

    PubMed

    Sergeeva, A; He, H; Ruisaard, K; St John, L; Alatrash, G; Clise-Dwyer, K; Li, D; Patenia, R; Hong, R; Sukhumalchandra, P; You, M J; Gagea, M; Ma, Q; Molldrem, J J

    2016-07-01

    The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a high-affinity T-cell receptor-like murine monoclonal antibody, 8F4, that binds to the PR1/HLA-A2 complex, mediates lysis of AML and inhibits leukemia colony formation. Here, we explored whether 8F4 was active in vivo against chemotherapy-resistant AML, including secondary AML. In a screening model, coincubation of AML with 8F4 ex vivo prevented engraftment of all tested AML subtypes in immunodeficient NSG (NOD scid IL-2 receptor γ-chain knockout) mice. In a treatment model of established human AML, administration of 8F4 significantly reduced or eliminated AML xenografts and extended survival compared with isotype antibody-treated mice. Moreover, in secondary transfer experiments, mice inoculated with bone marrow from 8F4-treated mice showed no evidence of AML engraftment, supporting the possible activity of 8F4 against the subset of AML with self-renewing potential. Our data provide evidence that 8F4 antibody is highly active in AML, including chemotherapy-resistant disease, supporting its potential use as a therapeutic agent in patients with AML.

  5. A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma.

    PubMed

    Planagumà, Jesús; Díaz-Fuertes, María; Gil-Moreno, Antonio; Abal, Miguel; Monge, Marta; García, Angel; Baró, Teresa; Thomson, Timothy M; Xercavins, Jordi; Alameda, Francesc; Reventós, Jaume

    2004-12-15

    Endometrial carcinoma is the most common gynecological malignant disease in industrialized countries. Two clinicopathological types of endometrial carcinoma have been described, based on estrogen relation and grade: endometrioid carcinoma (EEC) and non-EEC (NEEC). Some of the molecular events that occur during the development of endometrial carcinoma have been characterized, showing a dualistic genetic model for EEC and NEEC. However, the molecular bases for endometrial tumorigenesis are not clearly elucidated. In the present work, we attempted to identify new genes that could trigger cell transformation in EEC. We analyzed the differential gene expression profile between tumoral and nontumoral endometrial specimens with cDNA array hybridization. Among the 53 genes for which expression was found to be altered in EEC, the acute myeloid leukemia proto-oncogene, RUNX1/AML1, was one of the most highly up-regulated. The gene expression levels of RUNX1/AML1 were quantified by real-time quantitative PCR, and protein levels were characterized by tissue array immunohistochemistry. Real-time quantitative PCR validated RUNX1/AML1 up-regulation in EEC and demonstrated a specific and significantly stronger up-regulation in those tumor stages associated with myometrial invasion. Furthermore, tissue array immunohistochemistry showed that RUNX1/AML1 up-regulation correlates to the process of tumorigenesis, from normal atrophic endometrium to simple and complex hyperplasia and then, on to carcinoma. These results demonstrate for the first time the up-regulation of RUNX1/AML1 in EEC correlating with the initial steps of myometrial infiltration.

  6. CHK1 as a therapeutic target to bypass chemoresistance in AML.

    PubMed

    David, Laure; Fernandez-Vidal, Anne; Bertoli, Sarah; Grgurevic, Srdana; Lepage, Benoît; Deshaies, Dominique; Prade, Naïs; Cartel, Maëlle; Larrue, Clément; Sarry, Jean-Emmanuel; Delabesse, Eric; Cazaux, Christophe; Didier, Christine; Récher, Christian; Manenti, Stéphane; Hoffmann, Jean-Sébastien

    2016-09-13

    The nucleoside analog cytarabine, an inhibitor of DNA replication fork progression that results in DNA damage, is currently used in the treatment of acute myeloid leukemia (AML). We explored the prognostic value of the expression of 72 genes involved in various aspects of DNA replication in a set of 198 AML patients treated by cytarabine-based chemotherapy. We unveiled that high expression of the DNA replication checkpoint gene CHEK1 is a prognostic marker associated with shorter overall, event-free, and relapse-free survivals and determined that the expression of CHEK1 can predict more frequent and earlier postremission relapse. CHEK1 encodes checkpoint kinase 1 (CHK1), which is activated by the kinase ATR when DNA replication is impaired by DNA damage. High abundance of CHK1 in AML patient cells correlated with higher clonogenic ability and more efficient DNA replication fork progression upon cytarabine treatment. Exposing the patient cells with the high abundance of CHK1 to SCH900776, an inhibitor of the kinase activity of CHK1, reduced clonogenic ability and progression of DNA replication in the presence of cytarabine. These results indicated that some AML cells rely on an efficient CHK1-mediated replication stress response for viability and that therapeutic strategies that inhibit CHK1 could extend current cytarabine-based treatments and overcome drug resistance. Furthermore, monitoring CHEK1 expression could be used both as a predictor of outcome and as a marker to select AML patients for CHK1 inhibitor treatments. Copyright © 2016, American Association for the Advancement of Science.

  7. Mediator Kinase Inhibition Further Activates Super-Enhancer Associated Genes in AML

    PubMed Central

    Nitulescu, Ioana I.; Tangpeerachaikul, Anupong; Poss, Zachary C.; Da Silva, Diogo H.; Caruso, Brittany T.; Arefolov, Alexander; Fadeyi, Olugbeminiyi; Christie, Amanda L.; Du, Karrie; Banka, Deepti; Schneider, Elisabeth V.; Jestel, Anja; Zou, Ge; Si, Chong; Ebmeier, Christopher C.; Bronson, Roderick T.; Krivtsov, Andrei V.; Myers, Andrew G.; Kohl, Nancy E.; Kung, Andrew L.; Armstrong, Scott A.; Lemieux, Madeleine E.; Taatjes, Dylan J.; Shair, Matthew D.

    2015-01-01

    Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors (TFs), and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling TFs and oncogenes 1, 2. BRD4 and CDK7 are positive regulators of SE-mediated transcription3,4,5. In contrast, negative regulators of SE-associated genes have not been well described. Here we report that Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We determined that the natural product cortistatin A (CA) selectively inhibited Mediator kinases, had antileukaemic activity in vitro and in vivo, and disproportionately induced upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the TFs CEBPA, IRF8, IRF1 and ETV6 6, 7, 8. The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has antileukaemic activity. Individually increasing or decreasing expression of these TFs suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types and can be pharmacologically targeted as a therapeutic approach to AML. PMID:26416749

  8. Development of ZMYM2-FGFR1 driven AML in human CD34+ cells in immunocompromised mice.

    PubMed

    Ren, Mingqiang; Qin, Haiyan; Wu, Qing; Savage, Natasha M; George, Tracy I; Cowell, John K

    2016-08-15

    Acute myelogenous leukemia (AML) has an overall poor survival rate and shows considerable molecular heterogeneity in its etiology. In the WHO classification there are >50 cytogenetic subgroups of AML, many showing highly specific chromosome translocations that lead to constitutive activation of individual kinases. In a rare stem cell leukemia/lymphoma syndrome, translocations involving 8p11 lead to constitutive activation of the fibroblast growth factor receptor 1 (FGFR1) kinase. This disorder shows myeloproliferative disease with almost invariable progresses to AML and conventional therapeutic strategies are largely unsuccessful. Because of the rare nature of this syndrome, models that faithfully recapitulate the human disease are needed to evaluate therapeutic strategies. The t(8;13)(p11;q12) chromosome translocation is most common rearrangement seen in this syndrome and creates a ZMYM2-FGFR1 chimeric kinase. To understand more about the molecular etiology of AML induced by this particular rearrangement, we have created a model human CD34+ cells transplanted into immunocompromized mice which develop myeloproliferative disease that progresses to AML with a long (>12 months) latency period. As in humans, these mice show hepatospenomegaly, hypercellular bone marrow and a CD45 + CD34 + CD13+ immunophenotype. Molecular studies demonstrate upregulation of genes such as KLF4 and FLT3 that promote stemness, and overexpression of MYC, which is associated with suppression of myeloid cell differentiation. This murine model, therefore, provides an opportunity to develop therapeutic strategies against the most common subtype within these FGFR1 driven neoplasms and study the molecular etiology in more depth.

  9. Childhood leukemia genetic bottleneck phenomenon related to TEL-AML1: the postulation by a mathematical model.

    PubMed

    Ivanovski, Petar; Ivanovski, Ivan; Nikolić, Dimitrije; Jovanović, Ivana

    2012-03-01

    Childhood leukemia bottleneck phenomenon is the most mysterious corollary of the prenatal origin discovery of leukemogenic chromosome translocations. The bottleneck is evidence that leukemia initiation, by in utero acquired chromosome translocations that generate functional fusion genes, is far more common than the incidence rate of corresponding leukemia. For childhood TEL-AML1(+) acute lymphoblastic leukemia (ALL) this equates to approximately 100 times. Practically this means that among a hundred children born with TEL-AML1 fusion gene, only one child will later in its life develop ALL. The key data necessary for unraveling of this mystery were discovered in 2002. It was the level of TEL-AML1(+) cells’ frequency. The bottleneck is caused by the very low body TEL-AML1(+) cell count. Only one out of a thousand B cells carries TEL-AML1 fusion gene. TEL-AML1(+) body cell count is low because TEL-AML1 fusion is generated at cell level of 10(-3) to 10(-4) just during the late fetal lymphopoiesis i.e. after the 36th gestational week.

  10. Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation.

    PubMed

    Radivoyevitch, T; Sachs, R K; Gale, R P; Molenaar, R J; Brenner, D J; Hill, B T; Kalaycio, M E; Carraway, H E; Mukherjee, S; Sekeres, M A; Maciejewski, J P

    2016-02-01

    Risks of acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS) are known to increase after cancer treatments. Their rise-and-fall dynamics and their associations with radiation have, however, not been fully characterized. To improve risk definition we developed SEERaBomb R software for Surveillance, Epidemiology and End Results second cancer analyses. Resulting high-resolution relative risk (RR) time courses were compared, where possible, to results of A-bomb survivor analyses. We found: (1) persons with prostate cancer receiving radiation therapy have increased RR of AML and MDS that peak in 1.5-2.5 years; (2) persons with non-Hodgkin lymphoma (NHL), lung and breast first cancers have the highest RR for AML and MDS over the next 1-12 years. These increased RR are radiation specific for lung and breast cancer but not for NHL; (3) AML latencies were brief compared to those of A-bomb survivors; and (4) there was a marked excess risk of acute promyelocytic leukemia in persons receiving radiation therapy. Knowing the type of first cancer, if it was treated with radiation, the interval from first cancer diagnosis to developing AML or MDS, and the type of AML, can improve estimates of whether AML or MDS cases developing in this setting are due to background versus other processes.

  11. Outcome of myeloablative allogeneic peripheral blood hematopoietic stem cell transplantation for refractory/relapsed AML patients in NR status.

    PubMed

    Liu, Na; Ning, Hong-Mei; Hu, Liang-Ding; Jiang, Min; Xu, Chen; Hu, Jiang-Wei; Wang, Jun; Li, Yu-Hang; Li, Bo-Tao; Lou, Xiao; Yang, Fan; Chen, Jian-Lin; Su, Yong-Feng; Li, Meng; Wang, Hong-Ye; Ren, Jing; Feng, Yue-Qian; Zhang, Bin; Wang, Dan-Hong; Chen, Hu

    2015-12-01

    To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3-year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group.

  12. Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model.

    PubMed

    Qin, H; Malek, S; Cowell, J K; Ren, M

    2016-10-27

    Acute myeloid leukemia (AML) is a heterogeneous disease comprising a large number of subtypes defined by specific chromosome abnormalities. One such subtype carries the t(6;9)(p22;q34) chromosome rearrangement, which leads to expression of the DEK-NUP214 chimeric gene, and has a particularly poor outcome. To provide a better understanding of the molecular etiology of these relatively rare individual AML variants, it is necessary to generate in vivo models, which can also serve as a means to evaluate targeted therapies based on their specific genetic abnormalities. Here, we describe the development of a human cell AML, generated in CD34+ human hematopoietic progenitor cells xenografted into immunocompromised mice that express human myeloid cell growth factors. Within 6 months, these mice develop a human cell AML with phenotypic characteristics of the primary t(6;9) disease and a CD45+CD13+CD34+CD38+ immunophenotype. Gene expression studies show that members of the HOX family of genes (HOXA9, 10, B3, B4 and PBX3) are highly upregulated in the AML from this mouse model as well as from primary human t(6;9) AML. Gene expression analysis also identified several other significantly disregulated pathways involving KRAS, BRCA1 and ALK, for example. This is the first report of a humanized model of the DEK-NUP214 disease and provides a means to study the development and treatment of this particular subtype of AML.

  13. Behandlungspräferenzen für Biologika bei Psoriasis: erfahrene Patienten legen Wert auf Nachhaltigkeit.

    PubMed

    Kromer, Christian; Peitsch, Wiebke K; Herr, Raphael; Schmieder, Astrid; Sonntag, Diana; Schaarschmidt, Marthe-Lisa

    2017-02-01

    Die Therapiezufriedenheit kann durch die Berücksichtigung von Patientenpräferenzen in der gemeinsamen Entscheidungsfindung verbessert werden. Kürzlich untersuchten wir Patientenpräferenzen für Eigenschaften von Biologika und fanden starke Präferenzen für Sicherheit und Wirksamkeit. Die vorliegende Studie hatte das Ziel, Auswirkungen von Therapieerfahrung auf diese Präferenzen zu erheben. Präferenzen für Ergebnis- (Wahrscheinlichkeit einer 50%igen und 90%igen Verbesserung, Zeit bis zum Ansprechen, Nachhaltigkeit des Erfolgs, Wahrscheinlichkeit von leichten und schweren Nebenwirkungen und Wahrscheinlichkeit eines ACR-20-Ansprechens) und Prozesseigenschaften (Behandlungsort, Behandlungshäufigkeit, Zeitaufwand und Applikationsweise) wurden bei 200 Teilnehmern mit mittelschwerer bis schwerer Psoriasis mit Hilfe von Conjoint-Analyse ermittelt. Der Einfluss aktueller und früherer Therapien, der Krankheitsdauer und der Behandlungszufriedenheit auf die "Relative Importance Scores" wurde durch Varianz-analysen, Post-hoc-Tests und multivariate Regressionen bestimmt. Teilnehmer, die aktuell eine topische Therapie (p = 0,02) oder eine Phototherapie (p = 0,032) erhielten, hielten den Zeitaufwand der Behandlung für wichtiger als andere. Diejenigen, denen zuvor traditionelle Systemtherapien (p = 0,028) oder Biologika (p = 0,044) verordnet worden waren, legten mehr Wert auf die Nachhaltigkeit als andere. Diese Eigenschaft gewann mit steigender Anzahl zuvor verabreichter systemischer Therapien (p = 0,045) und längerer Krankheitsdauer (p = 0,018) an Bedeutung. Patientenpräferenzen für Biologika variieren abhängig von der Therapieerfahrung und Krankheitsdauer. Diese Aspekte sollten bei der gemeinsamen Entscheidungsfindung berücksichtigt werden. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  14. Chemogenomic landscape of RUNX1-mutated AML reveals importance of RUNX1 allele dosage in genetics and glucocorticoid sensitivity.

    PubMed

    Simon, Laura; Lavallée, Vincent-Philippe; Bordeleau, Marie-Eve; Krosl, Jana; Baccelli, Irene; Boucher, Geneviève; Lehnertz, Bernhard; Chagraoui, Jalila; MacRae, Tara; Ruel, Réjean; Chantigny, Yves A; Lemieux, Sébastien; Marinier, Anne; Hébert, Josée; Sauvageau, Guy

    2017-08-30

    RUNX1-mutated (RUNX1mut) Acute Myeloid Leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and for the design of efficient therapeutic strategies for this disease. Towards this goal, we further dissected the mutational spectrum and gene expression profile of RUNX1mut AML and correlated these results to drug sensitivity to identify novel compounds targeting this AML subgroup. RNA-sequencing of 47 RUNX1mut primary AML specimens was performed and sequencing results were compared to those of RUNX1 wild-type samples. Chemical screens were also conducted using RUNX1mut specimens to identify compounds selectively affecting the viability of RUNX1mut AML. We show that samples with no remaining RUNX1 wild-type allele are clinically and genetically distinct and display a more homogeneous gene expression profile. Chemical screening revealed that most RUNX1mut specimens are sensitive to glucocorticoids (GCs) and we confirmed that GCs inhibit AML cell proliferation through their interaction with the Glucocorticoid Receptor (GR). We observed that specimens harboring RUNX1 mutations expected to result in low residual RUNX1 activity are most sensitive to GCs, and that co-associating mutations as well as that GR levels contribute to GC sensitivity. Accordingly, acquired glucocorticoid sensitivity was achieved by negatively regulating RUNX1 expression in human AML cells. Our findings show the profound impact of RUNX1 allele dosage on gene expression profile and glucocorticoid sensitivity in AML, thereby opening opportunities for preclinical testing which may lead to drug repurposing and improved disease characterization. Copyright ©2017, American Association for Cancer Research.

  15. Classification of Acute Myelogenous Leukemia (AML M2 and AML M3) using Momentum Back Propagation from Watershed Distance Transform Segmented Images

    NASA Astrophysics Data System (ADS)

    Suryani, Esti; Wiharto; Palgunadi, Sarngadi; Nurcahya Pradana, TP

    2017-01-01

    This study uses image processing to analyze white blood cell with leukemia indicated that includes the identification, analysis of shapes and sizes, as well as white blood cell count indicated the symptoms of leukemia. A case study in this research was blood cells, from the type of leukemia Acute Myelogenous Leukemia (AML), M2 and M3 in particular. Image processing operations used for segmentation by utilizing the color conversion from RGB (Red, Green dab Blue) to obtain white blood cell candidates. Furthermore, the white blood cells candidates are separated by other cells with active contour without edge. WBC (White Blood Cell) results still have intersected or overlap condition. Watershed distance transform method can separate overlap of WBC. Furthermore, the separation of the nucleus from the cytoplasm using the HSI (Hue Saturation Intensity). The further characteristic extraction process is done by calculating the area WBC, WBC edge, roundness, the ratio of the nucleus, the mean and standard deviation of pixel intensities. The feature extraction results are used for training and testing in determining the classification of AML: M2 and M3 by using the momentum backpropagation algorithm. The classification process is done by testing the numeric data input from the feature extraction results that have been entered in the database. K-Fold validation is used to divide the amount of training data and to test the classification of AML M2 and M3. The experiment results of eight images trials, the result, was 94.285% per cell accuracy and 75% per image accuracy

  16. Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by Toll-like receptor (TLR) agonists.

    PubMed

    Zhong, RuiKun; Li, Hongying; Messer, Karen; Lane, Thomas A; Zhou, Jiehua; Ball, Edward D

    2015-06-01

    This study investigated whether TNF-α, Toll-like receptors (TLRs) 7/8 agonist resiquimod (R848), the TLR4 agonist lipopolysaccharide (LPS) and their combinations can enhance autologous AML-reactive T cell generation in an in vitro culture. AML peripheral blood or bone marrow mononuclear cells were cultured in medium supplemented with GM-CSF/IL-4 to induce dendritic cell (DC) differentiation of AML blasts (AML-DC). The impact of TNF-α, LPS, R848 and their combinations on AML-DC cultures was analyzed. Significantly enhanced CD80, CD40, CD83, CD54, HLA-DR and CD86 expression of AML cells was observed by addition of TNF-α, LPS, R848 alone or combinations. Induced CD80 expression of AML cells was significantly higher through the combination of TNF-α, LPS and R848 (T + L + R) than that by T alone. CTL induced from T + L + R, T + R, T + L, L + R and R, but not T, L alone stimulated cultures showed significantly higher IFN-γ release than the medium control in response to autologous AML cells. IFN-γ release by T + L + R was significantly higher than T or L alone, and T + R was significantly higher than T alone. CTL generated from T + L + R, T + L, T + R, L + R and L alone exerted significantly higher AML cell killing than medium control. AML cell killing by T + L + R and T + R was significantly higher than T or R alone. These results indicate that the combination of T + L + R induces a significantly enhanced antigen presentation effect of AML-DC. We speculate that the complementary effects of reagent combinations may better address the heterogeneity of responses to any single agent in AML cells from different patients.

  17. Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling.

    PubMed

    Taskesen, Erdogan; Havermans, Marije; van Lom, Kirsten; Sanders, Mathijs A; van Norden, Yvette; Bindels, Eric; Hoogenboezem, Remco; Reinders, Marcel J T; Figueroa, Maria E; Valk, Peter J M; Löwenberg, Bob; Melnick, Ari; Delwel, Ruud

    2014-05-22

    Mutations in splice factor (SF) genes occur more frequently in myelodysplastic syndromes (MDS) than in acute myeloid leukemias (AML). We sequenced complementary DNA from bone marrow of 47 refractory anemia with excess blasts (RAEB) patients, 29 AML cases with low marrow blast cell count, and 325 other AML patients and determined the presence of SF-hotspot mutations in SF3B1, U2AF35, and SRSF2. SF mutations were found in 10 RAEB, 12 AML cases with low marrow blast cell count, and 25 other AML cases. Our study provides evidence that SF-mutant RAEB and SF-mutant AML are clinically, cytologically, and molecularly highly similar. An integrated analysis of genomewide messenger RNA (mRNA) expression profiling and DNA-methylation profiling data revealed 2 unique patient clusters highly enriched for SF-mutant RAEB/AML. The combined genomewide mRNA expression profiling/DNA-methylation profiling signatures revealed 1 SF-mutant patient cluster with an erythroid signature. The other SF-mutant patient cluster was enriched for NRAS/KRAS mutations and showed an inferior survival. We conclude that SF-mutant RAEB/AML constitutes a related disorder overriding the artificial separation between AML and MDS, and that SF-mutant RAEB/AML is composed of 2 molecularly and clinically distinct subgroups. We conclude that SF-mutant disorders should be considered as myeloid malignancies that transcend the boundaries of AML and MDS.

  18. Dual functions of the AML1/Evi-1 chimeric protein in the mechanism of leukemogenesis in t(3;21) leukemias.

    PubMed Central

    Tanaka, T; Mitani, K; Kurokawa, M; Ogawa, S; Tanaka, K; Nishida, J; Yazaki, Y; Shibata, Y; Hirai, H

    1995-01-01

    The chromosomal translocation t(3;21)(q26;q22), which is found in blastic crisis in chronic myelogenous leukemias and myelodysplastic syndrome-derived leukemias, produces AML1/Evi-1 chimeric transcription factor and is thought to play important roles in acute leukemic transformation of hemopoietic stem cells. We report here the functional analyses of AML1/Evi-1. It was revealed that AML1/Evi-1 itself does not alter the transactivation level through mouse polyomavirus enhancer-binding protein 2 (PEBP2; PEA2) sites (binding site of AML1) but dominantly suppresses the transactivation by intact AML1, which is assumed to be a stimulator of myeloid cell differentiation. DNA-binding competition is a putative mechanism of such dominant negative effects of AML1/Evi-1 because it binds to PEBP2 sites with higher affinity than AML1 does. Furthermore, AML1/Evi-1 stimulated c-fos promoter transactivation and increased AP-1 activity, as Evi-1 (which is not normally expressed in hemopoietic cells) did. Experiments using deletion mutants of AML1/Evi-1 showed that these two functions are mutually independent because the dominant negative effects on intact AML1 and the stimulation of AP-1 activity are dependent on the runt domain (DNA-binding domain of AML1) and the zinc finger domain near the C terminus, respectively. Furthermore, we showed that AML1/Evi-1 blocks granulocytic differentiation, otherwise induced by granulocyte colony-stimulating factor, of 32Dcl3 myeloid cells. It was also suggested that both AML1-derived and Evi-1-derived portions of the fusion protein play crucial roles in this differentiation block. We conclude that the leukemic cell transformation in t(3;21) leukemias is probably caused by these dual functions of AML1/Evi-1 chimeric protein. PMID:7739522

  19. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial.

    PubMed

    Zhu, Hong-Hu; Zhang, Xiao-Hui; Qin, Ya-Zhen; Liu, Dai-Hong; Jiang, Hao; Chen, Huan; Jiang, Qian; Xu, Lan-Ping; Lu, Jin; Han, Wei; Bao, Li; Wang, Yu; Chen, Yu-Hong; Wang, Jing-Zhi; Wang, Feng-Rong; Lai, Yue-Yun; Chai, Jun-Yue; Wang, Li-Ru; Liu, Yan-Rong; Liu, Kai-Yan; Jiang, Bin; Huang, Xiao-Jun

    2013-05-16

    We aimed to improve the outcome of t(8;21) acute myeloid leukemia (AML) in the first complete remission (CR1) by applying risk-directed therapy based on minimal residual disease (MRD) determined by RUNX1/RUNX1T1 transcript levels. Risk-directed therapy included recommending allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk patients and chemotherapy/autologous-HSCT (auto-HSCT) for low-risk patients. Among 116 eligible patients, MRD status after the second consolidation rather than induction or first consolidation could discriminate high-risk relapse patients (P = .001). Allo-HSCT could reduce relapse and improve survival compared with chemotherapy for high-risk patients (cumulative incidence of relapse [CIR]: 22.1% vs 78.9%, P < .0001; disease-free survival [DFS]: 61.7% vs 19.6%, P = .001), whereas chemotherapy/auto-HSCT achieved a low relapse rate (5.3%) and high DFS (94.7%) for low-risk patients. Multivariate analysis revealed that MRD status and treatment choice were independent prognostic factors for relapse, DFS, and OS. We concluded that MRD status after the second consolidation may be the best timing for treatment choice. MRD-directed risk stratification treatment may improve the outcome of t(8;21) AML in CR1. This trial was registered at http://www.chictr.org as #ChiCTR-OCH-12002406.

  20. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.

    PubMed

    Döhner, Hartmut; Estey, Elihu; Grimwade, David; Amadori, Sergio; Appelbaum, Frederick R; Büchner, Thomas; Dombret, Hervé; Ebert, Benjamin L; Fenaux, Pierre; Larson, Richard A; Levine, Ross L; Lo-Coco, Francesco; Naoe, Tomoki; Niederwieser, Dietger; Ossenkoppele, Gert J; Sanz, Miguel; Sierra, Jorge; Tallman, Martin S; Tien, Hwei-Fang; Wei, Andrew H; Löwenberg, Bob; Bloomfield, Clara D

    2017-01-26

    The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease. © 2017 by The American Society of Hematology.

  1. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

    PubMed Central

    Estey, Elihu; Grimwade, David; Amadori, Sergio; Appelbaum, Frederick R.; Büchner, Thomas; Dombret, Hervé; Ebert, Benjamin L.; Fenaux, Pierre; Larson, Richard A.; Levine, Ross L.; Lo-Coco, Francesco; Naoe, Tomoki; Niederwieser, Dietger; Ossenkoppele, Gert J.; Sanz, Miguel; Sierra, Jorge; Tallman, Martin S.; Tien, Hwei-Fang; Wei, Andrew H.; Löwenberg, Bob; Bloomfield, Clara D.

    2017-01-01

    The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease. PMID:27895058

  2. The prognostic importance of polypharmacy in older adults treated for acute myelogenous leukemia (AML).

    PubMed

    Elliot, Kathleen; Tooze, Janet A; Geller, Rachel; Powell, Bayard L; Pardee, Timothy S; Ritchie, Ellen; Kennedy, LeAnne; Callahan, Kathryn E; Klepin, Heidi D

    2014-10-01

    We retrospectively evaluated the prognostic significance of polypharmacy and inappropriate medication use among 150 patients >60 years of age receiving induction chemotherapy for acute myelogenous leukemia (AML). After adjustment for age and comorbidity, increased number of medications at diagnosis (≥ 4 versus ≤ 1) was associated with increased 30-day mortality (OR=9.98, 95% CI=1.18-84.13), lower odds of complete remission status (OR=0.20, 95% CI=0.06-0.65), and higher overall mortality (HR=2.13, 95% CI=1.15-3.92). Inappropriate medication use (classified according to Beers criteria) was not significantly associated with clinical outcomes. Polypharmacy warrants further study as a modifiable marker of vulnerability among older adults with AML.

  3. The prognostic importance of polypharmacy in older adults treated for acute myelogenous leukemia (AML)

    PubMed Central

    Elliot, Kathleen; Tooze, Janet A.; Geller, Rachel; Powell, Bayard L.; Pardee, Timothy S.; Ritchie, Ellen; Kennedy, LeAnne; Callahan, Kathryn E.; Klepin, Heidi D.

    2014-01-01

    We retrospectively evaluated the prognostic significance of polypharmacy and inappropriate medication use among 150 patients >60 years of age receiving induction chemotherapy for acute myelogenous leukemia (AML). After adjustment for age and comorbidity, increased number of medications at diagnosis (≥4 vs. ≤1) was associated with increased 30-day mortality (OR=9.98, 95% CI=1.18–84.13), lower odds of complete remission status (OR=0.20, 95% CI=0.06–0.65), and higher overall mortality (HR=2.13, 95% CI=1.15–3.92). Inappropriate medication use (classified according to Beers criteria) was not significantly associated with clinical outcomes. Polypharmacy warrants further study as a modifiable marker of vulnerability among older adults with AML. PMID:25127690

  4. Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies.

    PubMed

    Oosterveld, Margriet; Suciu, Stefan; Muus, Petra; Germing, Ulrich; Delforge, Michel; Belhabri, Amin; Aul, Carlo; Selleslag, Dominik; Ferrant, Augustin; Marie, Jean-Pierre; Amadori, Sergio; Jehn, Ulrich; Mandelli, Franco; Hess, Uwe; Hellström-Lindberg, Eva; Cakmak-Wollgast, Songuel; Vignetti, Marco; Labar, Boris; Willemze, Roel; de Witte, Theo

    2015-01-01

    High-risk myelodysplastic syndrome (MDS) patients have usually a less favorable outcome after intensive treatment compared with de novo acute myeloid leukemia (AML) patients. This may reflect different disease-related and patient-related factors. The purpose of this analysis is to identify disease-specific prognostic factors and to develop prognostic scores for both patient groups. A total of 692 patients in the EORTC/GIMEMA AML-10 study and 289 patients in the CRIANT study received identical remission-induction and consolidation treatment. Estimated 5-year survival rate was 34 % in the AML-10 versus 27 % in the CRIANT study, and estimated disease-free survival was 40 % versus 28 %, respectively. In multivariate analysis, cytogenetic characteristics, white blood count, and age appeared prognostic for survival in both studies. French-American-British (FAB) subtype and performance status were prognostic in the AML-10 study only, whereas number of cytopenias and duration of antecedent hematologic disorder >6 months were prognostic in the CRIANT study only. The prognostic scores distinguish three groups with a 5-year survival rate of 54, 38, and 19 % in the AML-10 study versus 69, 37, and 5 % in the CRIANT study. The prognostic value of these scores has been validated on two external series. The new scoring systems form a practical tool to predict the outcome of individual MDS and AML patients treated with intensive antileukemic therapy.

  5. Differential diagnosis between AML infiltration, lymphoma and tuberculosis in a patient presenting with fever and mediastinal lymphadenopathy: A case report

    PubMed Central

    ZHAO, NA; YANG, JUN-JIE; ZHANG, GUANG-SEN

    2014-01-01

    The diagnosis of tuberculosis in immunocompromised hosts is often difficult as the hosts have atypical tuberculosis symptoms. The current study presents a case of scrofula and pulmonary tuberculosis with acute myelocytic leukemia (AML). As the disease became aggravated, the patient presented with fever, hemophagocytosis in the bone marrow, lymphadenopathy of the supraclavicular fossa, and mediastinal and nodular shadow in the chest by computed tomography. The symptoms presented successively or were coexistent, which made differentiation between tuberculosis, lymphoma, AML infiltration or other infections challenging. The diagnosis of tuberculosis was based on clinical and radiographic observations, morphological observation of the biopsies and the positive effect of antituberculosis drugs, while Ziehl-Neelsen stainings for acid fast bacilli were negative. The patient was treated with antituberculosis drugs, while receiving chemotherapy for AML. It is important to distinguish tuberculosis in adults with AML from other causes of fever, mediastinal masses in radiographic observations and hemophagocytosis in the bone marrow. PMID:24527075

  6. AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress

    PubMed Central

    Sriskanthadevan, Shrivani; Jeyaraju, Danny V.; Chung, Timothy E.; Prabha, Swayam; Xu, Wei; Skrtic, Marko; Jhas, Bozhena; Hurren, Rose; Gronda, Marcela; Wang, Xiaoming; Jitkova, Yulia; Sukhai, Mahadeo A.; Lin, Feng-Hsu; Maclean, Neil; Laister, Rob; Goard, Carolyn A.; Mullen, Peter J.; Xie, Stephanie; Penn, Linda Z.; Rogers, Ian M.; Dick, John E.; Minden, Mark D.

    2015-01-01

    Mitochondrial respiration is a crucial component of cellular metabolism that can become dysregulated in cancer. Compared with normal hematopoietic cells, acute myeloid leukemia (AML) cells and patient samples have higher mitochondrial mass, without a concomitant increase in respiratory chain complex activity. Hence these cells have a lower spare reserve capacity in the respiratory chain and are more susceptible to oxidative stress. We therefore tested the effects of increasing the electron flux through the respiratory chain as a strategy to induce oxidative stress and cell death preferentially in AML cells. Treatment with the fatty acid palmitate induced oxidative stress and cell death in AML cells, and it suppressed tumor burden in leukemic cell lines and primary patient sample xenografts in the absence of overt toxicity to normal cells and organs. These data highlight a unique metabolic vulnerability in AML, and identify a new therapeutic strategy that targets abnormal oxidative metabolism in this malignancy. PMID:25631767

  7. A Novel Tandem Duplication Assay to Detect Minimal Residual Disease in FLT3/ITD AML

    PubMed Central

    Lin, Ming-Tseh; Tseng, Li-Hui; Dudley, Jonathan C.; Riel, Stacey; Tsai, Harrison; Zheng, Gang; Pratz, Keith W.; Levis, Mark J.; Gocke, Christopher D.

    2015-01-01

    Background Internal tandem duplication (ITD) of the FLT3 gene is associated with poor prognosis in acute myeloid leukemia (AML) patients with a normal karyotype. The current standard PCR assay for FLT3/ITD detection is not sufficiently sensitive to monitor minimal residual disease (MRD). Clone-specific assays may have sufficient sensitivity but are not practical to implement, since each clone-specific primer/probe requires clinical validation. Objective To develop an assay for clinical molecular diagnostics laboratories to monitor MRD in FLT3/ITD AMLs. Methods We designed a simple novel assay, tandem duplication PCR (TD-PCR), and tested its sensitivity, specificity and clinical utility in FLT3/ITD AML patients. Results TD-PCR was capable of detecting a single ITD molecule and was applicable to 75% of ITD mutants tested. TD-PCR detected MRD in bone marrow prior to patient relapse. TD-PCR also identified low level ITD mutants not only in FLT3/ITD AMLs but also in initial diagnostic specimens reportedly negative by the standard assay in patients who progressed with the same ITDs detected by the TD-PCR assay. Conclusion Detection of MRD by TD-PCR may guide patient selection for early clinical intervention. In contrast to clone-specific approaches, TD-PCR assay can be more easily validated for MRD detection in clinical laboratories due to standardized primers and a universal positive control. In addition, our results on multi-clonality and low-level ITDs suggest that further studies are warranted to elucidate their clinical/biological significance. PMID:26446915

  8. Socioeconomic status (SES) and childhood acute myeloid leukemia (AML) mortality risk: Analysis of SEER data.

    PubMed

    Knoble, Naomi B; Alderfer, Melissa A; Hossain, Md Jobayer

    2016-10-01

    Socioeconomic status (SES) is a complex construct of multiple indicators, known to impact cancer outcomes, but has not been adequately examined among pediatric AML patients. This study aimed to identify the patterns of co-occurrence of multiple community-level SES indicators and to explore associations between various patterns of these indicators and pediatric AML mortality risk. A nationally representative US sample of 3651 pediatric AML patients, aged 0-19 years at diagnosis was drawn from 17 Surveillance, Epidemiology, and End Results (SEER) database registries created between 1973 and 2012. Factor analysis, cluster analysis, stratified univariable and multivariable Cox proportional hazards models were used. Four SES factors accounting for 87% of the variance in SES indicators were identified: F1) economic/educational disadvantage, less immigration; F2) immigration-related features (foreign-born, language-isolation, crowding), less mobility; F3) housing instability; and, F4) absence of moving. F1 and F3 showed elevated risk of mortality, adjusted hazards ratios (aHR) (95% CI): 1.07(1.02-1.12) and 1.05(1.00-1.10), respectively. Seven SES-defined cluster groups were identified. Cluster 1 (low economic/educational disadvantage, few immigration-related features, and residential-stability) showed the minimum risk of mortality. Compared to Cluster 1, Cluster 3 (high economic/educational disadvantage, high-mobility) and Cluster 6 (moderately-high economic/educational disadvantages, housing-instability and immigration-related features) exhibited substantially greater risk of mortality, aHR(95% CI)=1.19(1.0-1.4) and 1.23 (1.1-1.5), respectively. Factors of correlated SES-indicators and their pattern-based groups demonstrated differential risks in the pediatric AML mortality indicating the need of special public-health attention in areas with economic-educational disadvantages, housing-instability and immigration-related features.

  9. MK-2206 induces apoptosis of AML cells and enhances the cytotoxicity of cytarabine.

    PubMed

    Lu, Jeng-Wei; Lin, Yu-Min; Lai, Yen-Ling; Chen, Chien-Yuan; Hu, Chung-Yi; Tien, Hwei-Fang; Ou, Da-Liang; Lin, Liang-In

    2015-07-01

    Genetic alterations in the PI3K/AKT cascade have been linked to various human cancers including acute myeloid leukemia (AML) and have emerged to be promising targets for treatment. In this study, we explored the molecular mechanism and clinical implication of a specific allosteric AKT inhibitor, MK-2206, in the treatment of AML. Four leukemia cell lines, MV-4-11, MOLM-13, OCI/AML3, and U937, were used. Apoptosis and cell cycle distribution were determined by flow cytometry analysis. Expression of anti-apoptotic protein family and glycogen synthase kinase 3β (GSK3β) signaling was determined by western blotting. Drug combination effects of MK-2206 with cytarabine were evaluated by cell proliferation assay, and the combination index values were calculated by CompuSyn software. MK-2206 had no effect on normal peripheral blood mononuclear cells, but induced G1-phase arrest and apoptosis in leukemia cells. Among anti-apoptotic Bcl-2 family members, only myeloid cell leukemia-1 (Mcl-1) was significantly suppressed. Mcl-1 suppression by MK-2206 was closely associated with decreased GSK3β phosphorylation at Ser9, an event leads to GSK3β activation. Furthermore, the effect of MK-2206 on Mcl-1 downregulation was abolished by GSK3β inhibitor, lithium chloride and proteasome inhibitor, MG-132, suggesting that MK-2206 acted through a GSK3β-mediated, proteasome-dependent protein degradation. In addition, co-administration of MK-2206 with cytarabine could enhance the cytotoxic efficacy of cytarabine in leukemia cell lines. In conclusion, we have demonstrated that MK-2206 is an active agent in AML and its efficacy as in combination with cytarabine is implicated.

  10. Detection of the AML translocation (8;21) by two-color fluorescent in situ hybridization

    SciTech Connect

    Sacchi, N.; Magnani, I.; Kearney, L.

    1994-09-01

    In the translocation (8;21)(q22;q22) associated with acute myelogenous leukemia (AML), part of the long arm of chromosome 8 is reciprocally translocated onto chromosome 21. At the molecular level the translocation results in the fusion of the 5{prime} region of the AML1 gene on chromosome 21 and almost the entire CDR gene (also ETO or MTG8) on chromosome 8. To detection the translocation at the single cell level, we used two probes, a cosmid clone containing the first five exons of AML1 and a P1 clone containing the entire CDR gene. Hybridization of the two probes to the distal and proximal sides of the translocation breakpoint was expected to highlight the derivative 8q-chromosome in an interphase cell. To demonstrate the ability to identify the translocation in interphase cells using two-color FISH, these two probes were hybridized simultaneously to a cell line containing the 8;21 translocation, Kasumi-1. Each probe was detected with a different color so that their relationship in the sample could be determined within the same interphase cell. Simultaneous hybridization of the CDR and AML1 probes to interphase Kasumi-1 cells resulted in one orange and one green hybridization signal randomly located in the cell, from the hybridization to the normal 8 and 21 chromosomes, and one orange-green pair of signals from the close hybridization of the two probes to the fusion gene on the derivative 8q-chromosome, indicating the translocation. The translocation was identified by an abnormal pairing of the two differently colored signals in the same interphase cell. This technique allows for the detection of the translocation in all cells, not just those arrested in metaphase, and also permits the analysis of a small number of cells. Therefore, useful information can still be obtained from samples not suited for RT-PCR analysis and conventional cytogenetic techniques.

  11. The blind men and the AML elephant: can we feel the progress?

    PubMed Central

    Tauro, S

    2016-01-01

    The pharmacological therapy of non-promyelocytic acute myeloid leukemia (AML) has remained unchanged for over 40 years with an anthracycline–cytarabine combination forming the backbone of induction treatments. Nevertheless, the survival of younger patients has increased due to improved management of the toxicity of therapies including stem cell transplantation. Older patients and those with infirmity that precludes treatment-intensification have, however, not benefited from improvements in supportive care and continue to experience poor outcomes. An increased understanding of the genomic heterogeneity of AML raises the possibility of treatment-stratification to improve prognosis. Thus, efforts to identify agents with non-conventional anti-leukemic effects have paralleled those aiming to optimize leukemia cell-kill with conventional chemotherapy, resulting in a number of randomized controlled trials (RCT). In the last 18 months, RCTs investigating the effects of vosaroxin, azacitidine and gemtuzumab ozogamycin and daunorubicin dose have been reported with some studies indicating a statistically significant survival benefit with the investigational agent compared with standard therapy and potentially, a new era in AML therapeutics. Given the increasing costs of cancer care, a review of these studies, with particular attention to the magnitude of clinical benefit with the newer agents would be useful, especially for physicians treating patients in single-payer health systems. PMID:27176800

  12. MDS/AML del(11)(q14) Share Common Morphological Features Despite Different Chromosomal Breakpoints.

    PubMed

    Dambruoso, Irene; Invernizzi, Rosangela; Boni, Marina; Zappatore, Rita; Giardini, Ilaria; Cavigliano, Maria Paola; Rocca, Barbara; Calvello, Celeste; Bastia, Raffaella; Caresana, Marilena; Pasi, Francesca; Nano, Rosanna; Bernasconi, Paolo

    2017-02-01

    In myelodysplatic syndromes and acute myeloid leukemia (MDS/AML) deletion of the 11q14 region is a rare chromosomal defect (incidence: 0.6-1.0%), included within the intermediate risk criteria by the International Prognostic Scoring System. No fluorescence in situ hybridization (FISH) study has yet been performed to identify a common breakpoint region (CBR). In our study through FISH with bacterial artificial chromosomes and commercial probes, we analyzed seven patients with MDS/AML harboring 11q14 deletion on conventional cytogenetic analysis. FISH revealed deletions in five patients and amplifications in two. Three patients with deletion carried a CBR, two had a deletion involving a more centromeric breakpoint. These five patients exhibited multilineage dysplasia, blast cells with large round nuclei, loose chromatin, small and abundant nucleoli, and vacuolated cytoplasm with very thin Auer bodies. In conclusion, the morphological features which occur independently of the extent of the deletion are of multilineage dysplasia in MDS and leukemic blasts strongly reactive to peroxidase in AML; despite the variable size of the deleted area, some patients harbor a CBR.

  13. AML-loaded DC generate Th1-type cellular immune responses in vitro.

    PubMed

    Xing, D; Decker, W K; Li, S; Robinson, S N; Yang, H; Segal, H; O'Connor, S; Yao, X; Komanduri, K V; McMannis, J D; Jones, R B; de Lima, M; Champlin, R E; Shpall, E J

    2006-01-01

    The generation of AML-specific T-lymphocyte responses by leukemia-derived DC has been documented by multiple investigators and is being pursued clinically. An obstacle to widespread use of this strategy is that it has not been possible to generate leukemic DC from all patients, and an alternative approach is needed if the majority of leukemia patients are to receive therapeutic vaccination in conjunction with other treatment protocols. In the present study, we generated DC from CD14-selected monocytes isolated from healthy donor PBPC and loaded them with a total cell lysate from AML patient blasts. Immature in vitro-derived DC exhibited robust phagocytic activity, and mature DC demonstrated high expression of CD80, CD83, CD86 and the chemokine receptor CCR7, important for DC migration to local lymph nodes. Mature, Ag-loaded DC were used as APC for leukemia-specific cytotoxic T-lymphocyte (CTL) induction and demonstrated cytotoxic activity against leukemic targets. CTL lysis was Ag-specific, with killing of both allogeneic leukemic blasts and autologous DC loaded with allogeneic AML lysate. HLA-matched controls were not lysed in our system. These data support further research into the use of this strategy as an alternative approach to leukemia-derived DC vaccination.

  14. A multigene array for measurable residual disease detection in AML patients undergoing SCT

    PubMed Central

    Goswami, M; McGowan, K S; Lu, K; Jain, N; Candia, J; Hensel, N F; Tang, J; Calvo, K R; Battiwalla, M; Barrett, A J; Hourigan, C S

    2015-01-01

    AML is a diagnosis encompassing a diverse group of myeloid malignancies. Heterogeneous genetic etiology, together with the potential for oligoclonality within the individual patient, have made the identification of a single high-sensitivity marker of disease burden challenging. We developed a multiple gene measurable residual disease (MG-MRD) RQ–PCR array for the high-sensitivity detection of AML, retrospectively tested on 74 patients who underwent allo-SCT at the NHLBI in the period 1994–2012. MG-MRD testing on peripheral blood samples prior to transplantation demonstrated excellent concordance with traditional BM-based evaluation and improved risk stratification for post-transplant relapse and OS outcomes. Pre-SCT assessment by MG-MRD predicted all clinical relapses occurring in the first 100 days after allo-SCT compared with 57% sensitivity using WT1 RQ–PCR alone. Nine patients who were negative for WT1 prior to transplantation were correctly reclassified into a high-risk MG-MRD-positive group, associated with 100% post-transplant mortality. This study provides proof of principle that a multiple gene approach may be superior to the use of WT1 expression alone for AML residual disease detection. PMID:25665046

  15. Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation

    PubMed Central

    Link, Kevin A.; Lin, Shan; Shrestha, Mahesh; Bowman, Melissa; Wunderlich, Mark; Bloomfield, Clara D.; Huang, Gang; Mulloy, James C.

    2016-01-01

    Chromosomal translocation 8;21 is found in 40% of the FAB M2 subtype of acute myeloid leukemia (AML). The resultant in-frame fusion protein AML1-ETO (AE) acts as an initiating oncogene for leukemia development. AE immortalizes human CD34+ cord blood cells in long-term culture. We assessed the transforming properties of the alternatively spliced AE isoform AE9a (or alternative splicing at exon 9), which is fully transforming in a murine retroviral model, in human cord blood cells. Full activity was realized only upon increased fusion protein expression. This effect was recapitulated in the AE9a murine AML model. Cotransduction of AE and AE9a resulted in a strong selective pressure for AE-expressing cells. In the context of AE, AE9a did not show selection for increased expression, affirming observations of human t(8;21) patient samples where full-length AE is the dominant protein detected. Mechanistically, AE9a showed defective transcriptional regulation of AE target genes that was partially corrected at high expression. Together, these results bring an additional perspective to our understanding of AE function and highlight the contribution of oncogene expression level in t(8;21) experimental models. PMID:27457952

  16. Problems getting from the laboratory to the field: Reclamation of an AML site

    SciTech Connect

    Dick, W.A.; Stehouwer, R.C.; Bigham, J.M.; Beeghly, J.H.

    1994-12-31

    Acid and toxic abandoned mineland sites provide an opportunity whereby flue gas desulfurization (FGD) by-product can be beneficially used as a reclamation amendment material. Studies are needed to compare the effectiveness of FGD by-product, as compared with resoil, for reclamation purposes. Initial studies provided information about the chemical and physical properties of the FGD by-product and how to transport and blend the FGD by-product with yard waste compost. Greenhouse studies indicated that rates of 125 dry tons/acre of FGD and 50 dry tons/acre of yard waste compost would provide optimum results for reclamation of acid and toxic spoil contained at the Fleming abandoned mineland (AML) site. Their results showed that heavy metal loading rates were much lower using the FGD/compost mixture than using resoil material. Dioxin in the mixture was also less than the 5 ppt level considered as normal background. The technical problems of using FGD by-product for reclamation of an AML site were solved. However, considerable efforts to educate the public about the merits of reclaiming the Fleming AML site using this FGD/compost mixture were required before initiating field reclamation activities. Education efforts must continue if FGD by-products are to achieve general acceptance as a reclamation alternative to resoil in cases where resoil is of scarce supply.

  17. Chimeric antigen receptor T cell therapy in AML: How close are we?

    PubMed

    Gill, Saar

    2016-12-01

    The majority of patients presenting with acute myeloid leukemia (AML) initially respond to chemotherapy but post-remission therapy is required to consolidate this response and achieve long-term disease-free survival. The most effective form of post-remission therapy relies on T cell immunotherapy in the form of allogeneic hematopoietic cell transplantation (HCT). However, patients with active disease cannot usually expect to be cured with HCT. This inherent dichotomy implies that traditional T cell-based immunotherapy in the form of allogeneic HCT stops being efficacious somewhere between the measurable residual disease (MRD) and the morphologically obvious range. This is in part because the full power of T cells must be restrained in order to avoid lethal graft-versus-host disease (GVHD) and partly because only a sub-population of donor T cells are expected to be able to recognize AML cells via their T cell receptor. Chimeric antigen receptor (CAR) T cell therapy, most advanced in the treatment of patients with B-cell malignancies, may circumvent some of these limitations. However, major challenges remain to be overcome before CAR T cell therapy can be safely applied to AML.

  18. RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML.

    PubMed

    Crews, Leslie A; Balaian, Larisa; Delos Santos, Nathaniel P; Leu, Heather S; Court, Angela C; Lazzari, Elisa; Sadarangani, Anil; Zipeto, Maria A; La Clair, James J; Villa, Reymundo; Kulidjian, Anna; Storb, Rainer; Morris, Sheldon R; Ball, Edward D; Burkart, Michael D; Jamieson, Catriona H M

    2016-11-03

    Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors. In splicing reporter assays and pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. Therapeutic splicing modulation, together with monitoring splice isoform biomarkers of healthy HSPC aging versus LSC generation, may be employed safely and effectively to prevent relapse, the leading cause of leukemia-related mortality.

  19. NKG2D Signaling Leads to NK Cell Mediated Lysis of Childhood AML

    PubMed Central

    Ditthard, Kerstin; Lang, Peter; Mezger, Markus; Michaelis, Sebastian; Handgretinger, Rupert

    2015-01-01

    Natural killer cells have been shown to be relevant in the recognition and lysis of acute myeloid leukemia. In childhood acute lymphoblastic leukemia, it was shown that HLA I expression and KIR receptor-ligand mismatch significantly impact ALL cytolysis. We characterized 14 different primary childhood AML blasts by flow cytometry including NKG2D ligands. Further HLA I typing of blasts was performed and HLA I on the AML blasts was quantified. In two healthy volunteer NK cell donors HLA I typing and KIR genotyping were done. Blasts with high NKG2D ligand expression had significantly higher lysis by isolated NK cells. Grouping the blasts by NKG2D ligand expression led to a significant inverse correlation of HLA I expression and cytolysis in NKG2D low blasts. Furthermore, a significant positive correlation of NKG2D ligand expression and blast cytolysis was shown. No impact of KIR ligand-ligand mismatch was found but a significantly increased lysis of homozygous C2 blasts by KIR2DL1 negative NK cells (donor B) was revealed. In conclusion, NKG2D signaling leads to NK cell mediated lysis of childhood AML despite high HLA I expression. PMID:26236752

  20. Functional Pathway Analysis Using SCNP of FLT3 Receptor Pathway Deregulation in AML Provides Prognostic Information Independent from Mutational Status

    PubMed Central

    Cesano, Alessandra; Putta, Santosh; Rosen, David B.; Cohen, Aileen C.; Gayko, Urte; Mathi, Kavita; Woronicz, John; Hawtin, Rachael E.; Cripe, Larry; Sun, Zhuoxin; Tallman, Martin S.; Paietta, Elisabeth

    2013-01-01

    FMS-like tyrosine kinase 3 receptor (FLT3) internal tandem duplication (ITD) mutations result in constitutive activation of this receptor and have been shown to increase the risk of relapse in patients with acute myeloid leukemia (AML); however, substantial heterogeneity in clinical outcomes still exists within both the ITD mutated and unmutated AML subgroups, suggesting alternative mechanisms of disease relapse not accounted by FLT3 mutational status. Single cell network profiling (SCNP) is a multiparametric flow cytometry based assay that simultaneously measures, in a quantitative fashion and at the single cell level, both extracellular surface marker levels and changes in intracellular signaling proteins in response to extracellular modulators. We previously reported an initial characterization of FLT3 ITD-mediated signaling using SCNP. Herein SCNP was applied sequentially to two separate cohorts of samples collected from elderly AML patients at diagnosis. In the first (training) study, AML samples carrying unmutated, wild-type FLT3 (FLT3 WT) displayed a wide range of induced signaling, with a fraction having signaling profiles comparable to FLT3 ITD AML samples. Conversely, the FLT3 ITD AML samples displayed more homogeneous induced signaling, with the exception of patients with low (<40%) mutational load, which had profiles comparable to FLT3 WT AML samples. This observation was then confirmed in an independent (verification) cohort. Data from the second cohort were also used to assess the association between SCNP data and disease-free survival (DFS) in the context of FLT3 and nucleophosmin (NPM1) mutational status among patients who achieved complete remission (CR) to induction chemotherapy. The combination of SCNP read outs together with FLT3 and NPM1 molecular status improved the DFS prediction accuracy of the latter. Taken together, these results emphasize the value of comprehensive functional assessment of biologically relevant signaling pathways in AML

  1. The NAE inhibitor pevonedistat interacts with the HDAC inhibitor belinostat to target AML cells by disrupting the DDR.

    PubMed

    Zhou, Liang; Chen, Shuang; Zhang, Yu; Kmieciak, Maciej; Leng, Yun; Li, Lihong; Lin, Hui; Rizzo, Kathryn A; Dumur, Catherine I; Ferreira-Gonzalez, Andrea; Rahmani, Mohamed; Povirk, Lawrence; Chalasani, Sri; Berger, Allison J; Dai, Yun; Grant, Steven

    2016-05-05

    Two classes of novel agents, NEDD8-activating enzyme (NAE) and histone deacetylase (HDAC) inhibitors, have shown single-agent activity in acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS). Here we examined mechanisms underlying interactions between the NAE inhibitor pevonedistat (MLN4924) and the approved HDAC inhibitor belinostat in AML/MDS cells. MLN4924/belinostat coadministration synergistically induced AML cell apoptosis with or without p53 deficiency or FLT3-internal tandem duplication (ITD), whereas p53 short hairpin RNA (shRNA) knockdown or enforced FLT3-ITD expression significantly sensitized cells to the regimen. MLN4924 blocked belinostat-induced antiapoptotic gene expression through nuclear factor-κB inactivation. Each agent upregulated Bim, and Bim knockdown significantly attenuated apoptosis. Microarrays revealed distinct DNA damage response (DDR) genetic profiles between individual vs combined MLN4924/belinostat exposure. Whereas belinostat abrogated the MLN4924-activated intra-S checkpoint through Chk1 and Wee1 inhibition/downregulation, cotreatment downregulated multiple homologous recombination and nonhomologous end-joining repair proteins, triggering robust double-stranded breaks, chromatin pulverization, and apoptosis. Consistently, Chk1 or Wee1 shRNA knockdown significantly sensitized AML cells to MLN4924. MLN4924/belinostat displayed activity against primary AML or MDS cells, including those carrying next-generation sequencing-defined poor-prognostic cancer hotspot mutations, and CD34(+)/CD38(-)/CD123(+) populations, but not normal CD34(+) progenitors. Finally, combined treatment markedly reduced tumor burden and significantly prolonged animal survival (P < .0001) in AML xenograft models with negligible toxicity, accompanied by pharmacodynamic effects observed in vitro. Collectively, these findings argue that MLN4924 and belinostat interact synergistically by reciprocally disabling the DDR in AML/MDS cells. This strategy

  2. Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097.

    PubMed

    Weisberg, Ellen; Halilovic, Ensar; Cooke, Vesselina G; Nonami, Atsushi; Ren, Tao; Sanda, Takaomi; Simkin, Irene; Yuan, Jing; Antonakos, Brandon; Barys, Louise; Ito, Moriko; Stone, Richard; Galinsky, Ilene; Cowens, Kristen; Nelson, Erik; Sattler, Martin; Jeay, Sebastien; Wuerthner, Jens U; McDonough, Sean M; Wiesmann, Marion; Griffin, James D

    2015-10-01

    The tumor suppressor p53 is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (WT) p53, the HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell-cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor CGM097 to potently and selectively kill WT p53-expressing AML cells. The antileukemic effects of CGM097 were studied using cell-based proliferation assays (human AML cell lines, primary AML patient cells, and normal bone marrow samples), apoptosis, and cell-cycle assays, ELISA, immunoblotting, and an AML patient-derived in vivo mouse model. CGM097 potently and selectively inhibited the proliferation of human AML cell lines and the majority of primary AML cells expressing WT p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against oncogenic FLT3-expressing cells cultured both in the absence as well as the presence of cytoprotective stromal-secreted cytokines, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. These data suggest that CGM097 is a promising treatment for AML characterized as harboring WT p53 as a single agent, as well as in combination with other therapies targeting oncogene-activated pathways that drive AML.

  3. The US DOE/MIT Innovation Acceleration Competition

    SciTech Connect

    None, None

    2009-06-30

    The Competition asked student teams from several US Universities to propose business models, technological systems, and policy framework to accelerate the penetration of new vehicle and fuel technologies into the markets. In May 2009 the final selection of teams was announced and four of five finalist teams flew to Washington DC to present to the US Department of Energy. The five finalist teams were 1. Filter Sensing Technologies (FST) (MIT), 2. Flex Cathode Technology for Electric Vehicle Batteries, 3. Green Guidance (RPI), 4. Levant Power (MIT), and 5. Wind-Driven Paddlewheel Cylinder for Energy Storage in Freighter Trucks (Villanova). The five finalists entries are described.

  4. Hinderniserkennung und -verfolgung mit einer PMD-kamera im automobil

    NASA Astrophysics Data System (ADS)

    Schamm, Thomas; Vacek, Stefan; Natroshvilli, Koba; Marius Zöllner, J.; Dillmann, Rüdiger

    Die Detektion von Hindernissen vor dem Automobil ist eine Hauptanforderung an moderne Fahrerassistenzsysteme (FAS). In dieser Arbeit wird ein System vorgestellt, das mit Hilfe einer PMDKamera (Photomischdetektor) Hindernisse auf der Fahrspur erkennt und deren relevante Parameter bestimmt. Durch die PMD-Kamera werden zunächst 3D-Tiefenbilder der Fahrzeugumwelt generiert. Nach einem initialen Filterprozess werden im Tiefenbild mit Hilfe eines Bereichswachstumsverfahrens Hindernisse gesucht. Zur Stabilisierung des Verfahrens und zur Parameterberechnung wird ein Kaiman Filter eingesetzt. Das Ergebnis ist eine Liste aller Hindernisse im Fahrbereich des Automobils.

  5. Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.

    PubMed

    Vukovic, Milica; Guitart, Amelie V; Sepulveda, Catarina; Villacreces, Arnaud; O'Duibhir, Eoghan; Panagopoulou, Theano I; Ivens, Alasdair; Menendez-Gonzalez, Juan; Iglesias, Juan Manuel; Allen, Lewis; Glykofrydis, Fokion; Subramani, Chithra; Armesilla-Diaz, Alejandro; Post, Annemarie E M; Schaak, Katrin; Gezer, Deniz; So, Chi Wai Eric; Holyoake, Tessa L; Wood, Andrew; O'Carroll, Dónal; Ratcliffe, Peter J; Kranc, Kamil R

    2015-12-14

    Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance.

  6. Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model.

    PubMed

    Fischer, Meike; Schwieger, Maike; Horn, Stefan; Niebuhr, Birte; Ford, Anthony; Roscher, Susanne; Bergholz, Ulla; Greaves, Mel; Löhler, Jürgen; Stocking, Carol

    2005-11-17

    The t(12;21) translocation, generating the TEL/AML1 fusion protein, is the most common genetic lesion in childhood cancer. Using a bone marrow transplantation model, we demonstrate that TEL/AML1 expression impinges on normal hematopoietic differentiation, leading to the in vivo accumulation and persistence of an early progenitor compartment with a Sca1(+)/Kit(hi)/CD11b(+) phenotype and an increased self-renewal capacity, as documented by replating assays in vitro. Differentiation of these cells is not blocked, but the frequency of mature blood cells arising from TEL/AML1-transduced progenitors is low. Impaired differentiation is prominently observed in the pro-B-cell compartment, resulting in an proportional increase in early progenitors in vivo, consistent with the t(12;21) ALL phenotype. Despite the accumulation of both multipotent and B-cell progenitors in vivo, no leukemia induction was observed during an observation period of over 1 year. These results are consistent with findings in twins with concordant ALL, showing that TEL/AML1 generates a preleukemic clone in utero that persists for several years in a clinically covert fashion. Furthermore, our studies showed that the pointed domain of TEL/AML1, which recruits transcriptional repressors and directs oligomerization with either TEL/AML1 or wild-type TEL, was essential for the observed differentiation impairment and could not be replaced with another oligomerization domain.

  7. Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1 dependent manner.

    PubMed

    Man, Na; Tan, Yurong; Sun, Xiao-Jian; Liu, Fan; Cheng, Guoyan; Greenblatt, Sarah; Martinez, Camilo; Karl, Daniel L; Ando, Koji; Sun, Ming; Hou, Dan; Chen, Bingyi; Xu, Mingjiang; Yang, Feng-Chun; Chen, Zhu; Chen, Saijuan; Nimer, Stephen D; Wang, Lan

    2017-04-05

    AML1-ETO (AE), a fusion oncoprotein, generated by the t(8;21), can trigger acute myeloid leukemia (AML) in collaboration with mutations including c-Kit, ASXL1/2, FLT3, N-RAS, and K-RAS. Caspase-3, a key executor among its family, plays multiple roles in cellular processes, including hematopoietic development and leukemia progression. Caspase-3 was revealed to directly cleave AE in vitro, suggesting that AE may accumulate in a Caspase-3 compromised background and thereby accelerate leukemogenesis. Therefore, we developed a Caspase-3 knockout genetic mouse model of AML and found that loss of Caspase-3 actually delayed AML1-ETO9a (AE9a)-driven leukemogenesis, indicating that Caspase-3 may play distinct roles in the initiation and/or progression of AML. We report here that loss of Caspase-3 triggers a conserved, adaptive mechanism, namely autophagy (or macroautophagy), that acts to limit AE9a-driven leukemia. Furthermore, we identify ULK1 as a novel substrate of Caspase-3 and show that upregulation of ULK1 drives autophagy initiation in leukemia cells and that inhibition of ULK1 can rescue the phenotype induced by Caspase-3 deletion in vitro and in vivo Collectively, these data highlight Caspase-3 as an important regulator of autophagy in AML and demonstrate that the balance and selectivity between its substrates can dictate the pace of disease.

  8. Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through down-regulation of p19ARF.

    PubMed

    Nishimoto, Nahoko; Arai, Shunya; Ichikawa, Motoshi; Nakagawa, Masahiro; Goyama, Susumu; Kumano, Keiki; Takahashi, Tsuyoshi; Kamikubo, Yasuhiko; Imai, Yoichi; Kurokawa, Mineo

    2011-09-01

    Dysfunction of AML1/Runx1, a transcription factor, plays a crucial role in the development of many types of leukemia. Additional events are often required for AML1 dysfunction to induce full-blown leukemia; however, a mechanistic basis of their cooperation is still elusive. Here, we investigated the effect of AML1 deficiency on the development of MLL-ENL leukemia in mice. Aml1 excised bone marrow cells lead to MLL-ENL leukemia with shorter duration than Aml1 intact cells in vivo. Although the number of MLL-ENL leukemia-initiating cells is not affected by loss of AML1, the proliferation of leukemic cells is enhanced in Aml1-excised MLL-ENL leukemic mice. We found that the enhanced proliferation is the result of repression of p19(ARF) that is directly regulated by AML1 in MLL-ENL leukemic cells. We also found that down-regulation of p19(ARF) induces the accelerated onset of MLL-ENL leukemia, suggesting that p19(ARF) is a major target of AML1 in MLL-ENL leukemia. These results provide a new insight into a role for AML1 in the progression of leukemia.

  9. AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors.

    PubMed

    Nakagawa, Masahiro; Shimabe, Munetake; Watanabe-Okochi, Naoko; Arai, Shunya; Yoshimi, Akihide; Shinohara, Akihito; Nishimoto, Nahoko; Kataoka, Keisuke; Sato, Tomohiko; Kumano, Keiki; Nannya, Yasuhito; Ichikawa, Motoshi; Imai, Yoichi; Kurokawa, Mineo

    2011-12-15

    Functional deregulation of transcription factors has been found in many types of tumors. Transcription factor AML1/RUNX1 is one of the most frequent targets of chromosomal abnormalities in human leukemia and altered function of AML1 is closely associated with malignant transformation of hematopoietic cells. However, the molecular basis and therapeutic targets of AML1-related leukemia are still elusive. Here, we explored immediate target pathways of AML1 by in vitro synchronous inactivation in hematopoietic cells. We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling. Furthermore, inhibition of NF-κB signaling in leukemic cells with mutated AML1 efficiently blocks their growth and development of leukemia. These findings reveal a novel role for AML1 as a cytoplasmic attenuator of NF-κB signaling and indicate that NF-κB signaling is one of the promising therapeutic targets of hematologic malignancies with AML1 abnormality.

  10. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML.

    PubMed

    Knapper, Steven; Russell, Nigel; Gilkes, Amanda; Hills, Robert K; Gale, Rosemary E; Cavenagh, James D; Jones, Gail; Kjeldsen, Lars; Grunwald, Michael R; Thomas, Ian; Konig, Heiko; Levis, Mark J; Burnett, Alan K

    2017-03-02

    The clinical benefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and AML17 trials, patients with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years, were randomly assigned either to receive oral lestaurtinib (CEP701) or not after each of 4 cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days. The trials ran consecutively. Primary endpoints were overall survival in AML15 and relapse-free survival in AML17; outcome data were meta-analyzed. Five hundred patients were randomly assigned between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3-tyrosine kinase domain point mutations, and 2% both types. No significant differences were seen in either 5-year overall survival (lestaurtinib 46% vs control 45%; hazard ratio, 0.90; 95% CI 0.70-1.15; P = .3) or 5-year relapse-free survival (40% vs 36%; hazard ratio, 0.88; 95% CI 0.69-1.12; P = .3). Exploratory subgroup analysis suggested survival benefit with lestaurtinib in patients receiving concomitant azole antifungal prophylaxis and gemtuzumab ozogamicin with the first course of chemotherapy. Correlative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and indicated improved overall survival and significantly reduced rates of relapse in lestaurtinib-treated patients who achieved sustained greater than 85% FLT3 inhibition. In conclusion, combining lestaurtinib with intensive chemotherapy proved feasible in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefit. The improved clinical outcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-directed therapy alongside

  11. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial.

    PubMed

    Grimwade, D; Walker, H; Harrison, G; Oliver, F; Chatters, S; Harrison, C J; Wheatley, K; Burnett, A K; Goldstone, A H

    2001-09-01

    Acute myeloid leukemia (AML) in older adults carries a poor prognosis, and the optimum treatment remains to be determined. In younger patients, treatment stratification is frequently based upon diagnostic karyotype, which was the most important prognostic factor in the UK Medical Research Council (MRC) AML10 trial. Considered here is whether karyotype is also predictive in older adults; this is done by studying 1065 cases from MRC AML11 (median age, 66 years). Three prognostic groups were distinguished on the basis of response to induction therapy and overall survival (OS). Those with t(15;17), t(8;21), or inv(16) composed the favorable risk group. Overall, these abnormalities predicted a superior complete remission (CR) rate (72%), reflecting relatively low levels of resistant disease (RD) (8%), and lower relapse risk (RR) (56%) associated with superior OS (34% at 5 years). Normal karyotype (CR, 63%; RD, 17%; RR, 78%; OS, 15%) and other noncomplex abnormalities (CR, 53%; RD, 32%; RR, 85%; OS, 10%) composed the intermediate group; while complex karyotype predicted an extremely poor prognosis (CR, 26%; RD, 56%; RR, 91%; OS, 2%). Combining MRC AML10 and AML11 (n = 2677) revealed that the most favorable changes were rarer in older patients (younger than 55 years, 24%; 55 years or older, 7%), while complex abnormalities were more common (6% vs 13%). This study suggests that hierarchical cytogenetic classification identifies biologically distinct subsets of AML that are represented in all age groups. Furthermore, it highlights the importance of karyotype as a critical independent determinant of outcome in older patients with AML, providing a potential framework for stratified treatment approaches.

  12. MIT Orients Course Materials Online to K-12

    ERIC Educational Resources Information Center

    Cavanagh, Sean

    2008-01-01

    Many science and mathematics educators across the country are taking advantage of a Web site created by the Massachusetts Institute of Technology (MIT), the famed research university located in Cambridge, Massachusetts, which offers free video, audio, and print lectures and course material taken straight from the school's classes. Those resources…

  13. MIT Mints a Valuable New Form of Academic Currency

    ERIC Educational Resources Information Center

    Carey, Kevin

    2012-01-01

    The Massachusetts Institute of Technology (MIT) has invented or improved many world-changing things--radar, information theory, and synthetic self-replicating molecules, to name a few. Last month the university announced, to mild fanfare, an invention that could be similarly transformative, this time for higher education itself. It is called MITx.…

  14. MIT Mints a Valuable New Form of Academic Currency

    ERIC Educational Resources Information Center

    Carey, Kevin

    2012-01-01

    The Massachusetts Institute of Technology (MIT) has invented or improved many world-changing things--radar, information theory, and synthetic self-replicating molecules, to name a few. Last month the university announced, to mild fanfare, an invention that could be similarly transformative, this time for higher education itself. It is called MITx.…

  15. Numerische Berechnung von Wirbelstromproblemen mit der Cell-Methode

    NASA Astrophysics Data System (ADS)

    Frenner, K.; Rucker, W. M.

    2006-09-01

    In dieser Arbeit wird die Cell-Methode auf die quasistatischen Maxwellgleichungen angewendet. Dabei werden für die notwendige Transformation vom Primärgitter auf das duale Gitter reziproke Basisvektoren verwendet. Anhand der Felddiffusion der magnetischen Induktion in einen zylindrischen Leiter werden Ergebnisse der Cell-Methode mit einer analytischen Vergleichsrechnung präsentiert.

  16. The Creation of OpenCourseWare at MIT

    ERIC Educational Resources Information Center

    Abelson, Hal

    2008-01-01

    This paper traces the genesis of the MIT OpenCourseWare project from its initial strategic precursors in 1999 and 2000, through its launch in 2001 and its subsequent evolution. The story told here illuminates the interplay among institutional leadership, and strategic planning, and with university culture in launching major educational technology…

  17. Funktionelle Elektrostimulation Paraplegischer Patienten

    PubMed Central

    2014-01-01

    Functional Electrical Stimulation on Paraplegic Patients. We report on clinical and physiological effects of 8 months Functional Electrical Stimulation (FES) of quadriceps femoris muscle on 16 paraplegic patients. Each patient had muscle biopsies, CT-muscle diameter measurements, knee extension strength testing carried out before and after 8 months FES training. Skin perfusion was documented through infrared telethermography and xenon clearance, muscle perfusion was recorded through thallium scintigraphy. After 8 months FES training baseline skin perfusion showed 86 % increase, muscle perfusion was augmented by 87 %. Muscle fiber diameters showed an average increase of 59 % after 8 months FES training. Muscles in patients with spastic paresis as well as in patients with denervation showed an increase in aerob and anaerob muscle enzymes up to the normal range. Even without axonal neurotropic substances FES was able to demonstrate fiberhypertrophy, enzyme adaptation and intracellular structural benefits in denervated muscles. The increment in muscle area as visible on CT-scans of quadriceps femoris was 30 % in spastic paraplegia and 10 % in denervated patients respectively. FES induced changes were less in areas not directly underneath the surface electrodes. We strongly recommend the use of Kern’s current for FES in denervated muscles to induce tetanic muscle contractions as we formed a very critical opinion of conventional exponential current. In patients with conus-cauda-lesions FES must be integrated into modern rehabilitation to prevent extreme muscle degeneration and decubital ulcers. Using FES we are able to improve metabolism and induce positive trophic changes in our patients lower extremities. In spastic paraplegics the functions „rising and walking“ achieved through FES are much better training than FES ergometers. Larger muscle masses are activated and an increased heart rate is measured, therefore the impact on cardiovascular fitness and metabolism is much greater. This effectively addresses and prevents all problems which result from inactivity in paraplegic patients. PMID:26913132

  18. Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia.

    PubMed

    Roboz, Gail J; Montesinos, Pau; Selleslag, Dominik; Wei, Andrew; Jang, Jun-Ho; Falantes, Jose; Voso, Maria T; Sayar, Hamid; Porkka, Kimmo; Marlton, Paula; Almeida, Antonio; Mohan, Sanjay; Ravandi, Farhad; Garcia-Manero, Guillermo; Skikne, Barry; Kantarjian, Hagop

    2016-02-01

    Older patients with acute myeloid leukemia (AML) have worse rates of complete remission and shorter overall survival than younger patients. The epigenetic modifier CC-486 is an oral formulation of azacitidine with promising clinical activity in patients with AML in Phase I studies. The Phase III, randomized, double-blind, placebo-controlled QUAZAR AML Maintenance trial (CC-486-AML-001) examines CC-486 maintenance therapy (300 mg/day for 14 days of 28-day treatment cycles) for patients aged ≥55 years with AML in first complete remission. The primary end point is overall survival. Secondary end points include relapse-free survival, safety, health-related quality of life and healthcare resource utilization. This trial will investigate whether CC-486 maintenance can prolong remission and improve survival for older patients with AML.

  19. Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML.

    PubMed

    Rijal, Sewa; Fleming, Shaun; Cummings, Nik; Rynkiewicz, Natalie K; Ooms, Lisa M; Nguyen, Nhu-Y N; Teh, Tse-Chieh; Avery, Sharon; McManus, Julie F; Papenfuss, Anthony T; McLean, Catriona; Guthridge, Mark A; Mitchell, Christina A; Wei, Andrew H

    2015-04-30

    Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.

  20. Acquired TET2 mutation in one patient with familial platelet disorder with predisposition to AML led to the development of pre-leukaemic clone resulting in T2-ALL and AML-M0.

    PubMed

    Manchev, Vladimir T; Bouzid, Hind; Antony-Debré, Iléana; Leite, Betty; Meurice, Guillaume; Droin, Nathalie; Prebet, Thomas; Costello, Régis T; Vainchenker, William; Plo, Isabelle; Diop, M'boyba; Macintyre, Elizabeth; Asnafi, Vahid; Favier, Rémi; Baccini, Véronique; Raslova, Hana

    2016-12-20

    Familial platelet disorder with predisposition to acute myeloid leukaemia (FPD/AML) is characterized by germline RUNX1 mutations, thrombocytopaenia, platelet dysfunction and a risk of developing acute myeloid and in rare cases lymphoid T leukaemia. Here, we focus on a case of a man with a familial history of RUNX1(R174Q) mutation who developed at the age of 42 years a T2-ALL and, 2 years after remission, an AML-M0. Both AML-M0 and T2-ALL blast populations demonstrated a loss of 1p36.32-23 and 17q11.2 regions as well as other small deletions, clonal rearrangements of both TCRγ and TCRδ and a presence of 18 variants at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone, which gave rise to subclonal populations. Next generation sequencing (NGS) performed on peripheral blood-derived CD34(+) cells 5 years prior to T2-ALL development revealed only the missense TET2(P1962T) mutation at a frequency of 1%, which increases to more than 40% in fully transformed leukaemic T2-ALL and AML-M0 clones. This result suggests that TET2(P1962T) mutation in association with germline RUNX1(R174Q) mutation leads to amplification of a haematopoietic clone susceptible to acquire other transforming alterations.

  1. Monitoring Response and Resistance to the Novel Arsenical Darinaparsin in an AML Patient

    PubMed Central

    Nielsen, Torsten H.; Johnson, Nathalie; Garnier, Nicolas; Kwan, Stanley; Yao, Lu; Cocolakis, Eftihia; Hébert, Josée; Morgan, Robert A.; Paquet, Éric; Callahan, Kevin P.; Jordan, Craig T.; Assouline, Sarit; Miller, Wilson H.; Mann, Koren K.

    2012-01-01

    Acute myeloid leukemia (AML) with inversion of chromosome 3 is characterized by overexpression of EVI1 and carries a dismal prognosis. Arsenic-containing compounds have been described to be efficacious in malignancies overexpressing EVI1. Here, we describe a case of AML with inv(3)(q21q26.2) treated with the organic arsenical darinaparsin. Using a “personalized medicine approach,” two different arsenicals were screened for anti-leukemic effect against the patient’s cells ex vivo. The most promising compound, darinaparsin, was selected for in vivo treatment. Clinical effect was almost immediate, with a normalization of temperature, a stabilization of white blood cell (WBC) counts and an increased quality of life. Longitudinal monitoring of patient response and resistance incorporating significant correlative studies on patient-derived blood samples over the two cycles of darinaparsin given to this patient allowed us to evaluate potential mechanisms of response and resistance. The anti-leukemic effects of darinaparsin correlated with inhibition of the alternative NF-κB pathway and production of the inflammatory cytokine IL-8. Emergence of resistance was suspected during treatment cycle 2 and supported by xenograft studies in nude mice. Darinaparsin resistance correlated with an attenuation of the effect of treatment on the alternative NF-κB pathway. The results from this patient indicate that darinaparsin may be a good treatment option for inv(3) AML and that inhibition of the alternative NF-κB pathway may be predictive of response. Longitudinal monitoring of disease response as well as several correlative parameters allowed for the generation of novel correlations and predictors of response to experimental therapy in a heavily pretreated patient. PMID:23408639

  2. Cytarabine and clofarabine after high-dose cytarabine in relapsed or refractory AML patients.

    PubMed

    Scappini, Barbara; Gianfaldoni, Giacomo; Caracciolo, Francesco; Mannelli, Francesco; Biagiotti, Caterina; Romani, Claudio; Pogliani, Enrico M; Simonetti, Federico; Borin, Lorenza; Fanci, Rosa; Cutini, Ilaria; Longo, Giovanni; Susini, Maria Chiara; Angelucci, Emanuele; Bosi, Alberto

    2012-12-01

    Clofarabine has been shown to be effective in AML patients, either as single agent or, mainly, in association with intermediate dose cytarabine. Based on these reports, we conducted a preliminary study combining clofarabine and intermediate dose cytarabine in AML patients who relapsed or failed to respond to at least two induction therapies. We treated 47 patients affected by relapsed/refractory AML with a regimen including clofarabine at 22.5 mg/m(2) daily on days 1-5, followed after 3 hr by cytarabine at 1 g/m(2) daily on days 1-5. Ten patients received a further consolidation cycle with clofarabine at 22.5 mg/m(2) and cytarabine at 1 g/m(2) day 1-4. Among the 47 patients, 24/47 (51%) achieved a complete remission, 5/47 (10.5%) a partial response, 10/47 (21%) had a resistant disease, and 6/47 (13%) died of complications during the aplastic phase. The most frequent nonhematologic adverse events were vomiting, diarrhea, transient liver toxicity, febrile neutropenia, and infections microbiologically documented. Among the 24 patients who obtained a CR 13 underwent allogeneic bone marrow transplantation. In 14 patients, complete remission duration was shorter than 12 months, whereas 10 patients experienced longer complete remission duration. These very preliminary results suggest that clofarabine-cytarabine regimen is effective in this particularly poor prognosis category of patients, representing a potential "bridge" toward bone marrow transplant procedures. Safety data were consistent with previously reported salvage therapies. Further studies and a longer follow up are warranted.

  3. Optimizing outcomes following allogeneic hematopoietic progenitor cell transplantation in AML: the role of hypomethylating agents.

    PubMed

    Martino, Massimo; Fedele, Roberta; Moscato, Tiziana; Ronco, Francesca

    2013-07-01

    Aberrant DNA methylation is a key pathological mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and provides rationale for the clinical development of hypomethylating agents (HMAs) for the treatment of these diseases. One HMA, azacitidine (Vidaza®, Celgene Corp.), has demonstrated improved survival versus conventional care regimens in patients with intermediate-2/high-risk MDS and AML (20-30% blasts) and has a favorable tolerability profile. Emerging evidence indicates that azacitidine can have an immunomodulatory effect by, for example, increasing functional regulatory T-cell (Treg) numbers and killer-cell-immunoglobulin-like receptor expression. Allogeneic hematopoietic progenitor cell transplantation (allo HPCT) is the only potentially curative treatment approach in patients with advanced MDS or AML. Unfortunately, allo HPCT in these settings is limited because most patients are ineligible due to age/comorbidities, or are at a high risk of treatment failure due to disease relapse. Recent studies have shown that azacitidine after allo HPCT increases Treg numbers while inducing a cytotoxic CD8+ T-cell response, suggesting a potential mechanism for augmenting the graft-versus-leukemia (GvL) effect without increasing graft-versushost- disease (GVHD). In patients at a high risk of relapse following allo HPCT, pre-emptive azacitidine may help prevent/delay relapse. For patients who have relapsed following allo HPCT, azacitidine may be a salvage therapy option, either as monotherapy or in combination with donor lymphocyte infusions (DLI). In this mini-review, we discuss these emerging clinical data for HMAs in the post-allo HPCT regimens and highlight the possible future role of azacitidine in this setting.

  4. MRD in AML: does it already guide therapy decision-making?

    PubMed

    Ossenkoppele, Gert; Schuurhuis, Gerrit Jan

    2016-12-02

    Prognostic factors determined at diagnosis are predictive for outcome whereas achievement of morphological complete remission (CR) is still an important end point during treatment. Residual disease after therapy may reflect the sum of all diagnosis and postdiagnosis resistance mechanisms/factors; its measurement could hypothetically be very instrumental for guiding treatment. The possibility of defining residual disease (minimal residual disease [MRD]) far below the level of 5% blast cells is changing the landscape of risk classification. In this manuscript, the various methods, all different in sensitivity, specificity, and phase of development, to assess MRD are discussed. Currently, the 2 methods mostly used are flow cytometry-based immune MRD (multiparameter flow cytometry [MPFC]) and molecular MRD assessed by real-time quantitative polymerase chain reaction. Both have advantages and disadvantages that are summarized in detail. Many studies in children as well as adults already demonstrated that MRD detection by MPFC or molecular MRD provides strong prognostic information in acute myeloid leukemia (AML) after both induction and consolidation. These studies are summarized in this review. The general conclusion of this review is that a better definition of disease burden than morphological CR is now emerging. MRD assessed by flow or molecular techniques should become standard in every clinical trial in AML. Harmonization of antibody panels, introduction of single-cell tube systems (for determination of residual leukemic stem cells), and standardized analytical programs will pave the way for individual risk assessment and become a surrogate end point for survival in studies investigating new drugs, hopefully resulting in faster drug approval in AML.

  5. Comorbidity, age and mortality among adults treated intensively for acute myeloid leukemia (AML)

    PubMed Central

    Tawfik, Bernard; Pardee, Timothy; Isom, Scott; Sliesoraitis, Sarunas; Winter, Allison; Lawrence, Julia; Powell, Bayard L.; Klepin, Heidi D.

    2015-01-01

    Introduction Our goal was to characterize comorbidities among adults receiving intensive therapy for AML, and investigate their association with outcomes. Methods We retrospectively analyzed 277 consecutive patients with newly diagnosed AML treated intensively at the Comprehensive Cancer Center of Wake Forest University from 2002–2009. Pretreatment comorbidities were identified by ICD-9 codes and chart review. Comorbidity burden (modified Charlson Comorbidity Index [CCI]) and specific conditions were analyzed individually. Outcomes were overall survival (OS), remission, and 30-day mortality. Covariates included age, gender, cytogenetic characteristics, hemoglobin, white cell count, lactate dehydrogenase, body mass index, and insurance type. Cox proportional hazards models were used to evaluate OS; logistic regression was used for remission and 30-day mortality. Results In this series, 144 patients were ≥60 years old (median age 70 years, median survival 8.7 months) and 133 were <60 years (median age 47 years, median survival 23.1 months). Older patients had a higher comorbidity burden (CCI≥1 58% versus 26%, p<0.001). Prevalent comorbid conditions differed by age (diabetes 19.2% versus 7.5%; cardiovascular disease 12.5% versus 4.5%, for older versus younger patients, respectively). The CCI was not independently associated with OS or 30-day mortality in either age group. Among older patients, diabetes was associated with higher 30-day mortality (33.3% vs. 12.0% in diabetic vs. non diabetic patients, p =0.006). Controlling for age, cytogenetic characteristics and other comorbidities, the presence of diabetes increased the odds of 30-day mortality by 4.9 (CI 1.6–15.2) times. Discussion Diabetes is adversely associated with 30-day survival in older AML patients receiving intensive therapy. PMID:26527394

  6. Esculetin Downregulates the Expression of AML1-ETO and C-Kit in Kasumi-1 Cell Line by Decreasing Half-Life of mRNA.

    PubMed

    Sawney, Sharad; Arora, Rashi; Aggarwal, Kamal K; Saluja, Daman

    2015-01-01

    One of the most frequent genetic aberrations in acute myeloid leukemia (AML) is chromosomal translocation between AML1/RUNX1 on chromosome 21 and ETO gene on chromosome 8 resulting in the expression of chimeric oncogene AML1-ETO. Although patients with t(8;21) translocation have good prognosis, 5-year survival is observed only in 50% of the cases. AML1-ETO translocation is usually accompanied by overexpression of mutant C-Kit, a tyrosine kinase, which contributes to uncontrolled proliferation of premature blood cells leading to relapse and poor prognosis. We illustrate the potential use of esculetin on leukemic cell line, Kasumi-1, bearing t(8;21) translocation and mutated C-Kit gene. Esculetin decreases the expression of AML1-ETO at both protein and transcript level within 24 hours of treatment. Half-life of AML1-ETO mRNA was reduced from 7 hours to 1.5 hours. Similarly half-life of C-Kit mRNA was reduced to 2 hours from 5 hours in esculetin treated cells. Esculetin also perturbed the expression of ectopically expressed AML1-ETO in U937 cells. The decreased expression of AML1-ETO chimeric gene was associated with increased expression of LAT1 and RUNX3 genes, targets of AML1. We envisage that discovery of a drug candidate which could target both these mutated genes would be a considerable breakthrough for future application.

  7. Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes.

    PubMed

    Diaz de la Guardia, Rafael; Lopez-Millan, Belen; Lavoie, Jessie R; Bueno, Clara; Castaño, Julio; Gómez-Casares, Maite; Vives, Susana; Palomo, Laura; Juan, Manel; Delgado, Julio; Blanco, Maria L; Nomdedeu, Josep; Chaparro, Alberto; Fuster, Jose Luis; Anguita, Eduardo; Rosu-Myles, Michael; Menéndez, Pablo

    2017-06-06

    Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Esculetin Downregulates the Expression of AML1-ETO and C-Kit in Kasumi-1 Cell Line by Decreasing Half-Life of mRNA

    PubMed Central

    Sawney, Sharad; Arora, Rashi; Aggarwal, Kamal K.; Saluja, Daman

    2015-01-01

    One of the most frequent genetic aberrations in acute myeloid leukemia (AML) is chromosomal translocation between AML1/RUNX1 on chromosome 21 and ETO gene on chromosome 8 resulting in the expression of chimeric oncogene AML1-ETO. Although patients with t(8;21) translocation have good prognosis, 5-year survival is observed only in 50% of the cases. AML1-ETO translocation is usually accompanied by overexpression of mutant C-Kit, a tyrosine kinase, which contributes to uncontrolled proliferation of premature blood cells leading to relapse and poor prognosis. We illustrate the potential use of esculetin on leukemic cell line, Kasumi-1, bearing t(8;21) translocation and mutated C-Kit gene. Esculetin decreases the expression of AML1-ETO at both protein and transcript level within 24 hours of treatment. Half-life of AML1-ETO mRNA was reduced from 7 hours to 1.5 hours. Similarly half-life of C-Kit mRNA was reduced to 2 hours from 5 hours in esculetin treated cells. Esculetin also perturbed the expression of ectopically expressed AML1-ETO in U937 cells. The decreased expression of AML1-ETO chimeric gene was associated with increased expression of LAT1 and RUNX3 genes, targets of AML1. We envisage that discovery of a drug candidate which could target both these mutated genes would be a considerable breakthrough for future application. PMID:25861270

  9. DNMT3A R882 Mutations Predict a Poor Prognosis in AML: A Meta-Analysis From 4474 Patients.

    PubMed

    Yuan, Xiao-Qing; Peng, Li; Zeng, Wen-Jing; Jiang, Bin-Yuan; Li, Guan-Cheng; Chen, Xiao-Ping

    2016-05-01

    DNA (cytosine-5)-methyltransferase 3 alpha (DNMT3A) mutations were widely believed to be independently associated with inferior prognosis in acute myeloid leukemia (AML) patients. As dominant missense alterations in DNMT3A mutations, R882 mutations cause the focal hypomethylation phenotype. However, there remains debate on the influence of R882 mutations on AML prognosis. Thus, this meta-analysis aimed at further illustrating the prognostic power of DNMT3A R882 mutations in AML patients.Eligible studies were identified from 5 databases containing PubMed, Embase, Web of Science, Clinical Trials, and the Cochrane Library (up to October 25, 2015). Effects (hazard ratios [HRs] with 95% confidence interval [CI]) of relapse-free survival (RFS) and overall survival (OS) were pooled to estimate the prognostic power of mutant DNMT3A R882 in overall patients and subgroups of AML patients.Eight competent studies with 4474 AML patients including 694 with DNMT3A R882 mutations were included. AML patients with DNMT3A R882 mutations showed significant shorter RFS (HR = 1.40, 95% CI = 1.24-1.59, P < 0.001) and OS (HR = 1.47, 95% CI = 1.17-1.86, P = 0.001) in the overall population. DNMT3A R882 mutations predicted worse RFS and OS among the subgroups of patients under age 60 (RFS: HR = 1.44, 95% CI = 1.25-1.66, P < 0.001; OS: HR = 1.48, 95% CI = 1.15-1.90, P = 0.002), over age 60 (RFS: HR = 2.03, 95% CI = 1.40-2.93, P < 0.001; OS: HR = 1.85, 95% CI = 1.36-2.53, P < 0.001), cytogenetically normal (CN)-AML (RFS: HR = 1.52, 95% CI = 1.26-1.83, P < 0.001; OS: HR = 1.67, 95% CI = 1.16-2.41, P = 0.006), and non-CN-AML (RFS: HR = 1.96, 95% CI = 1.20-3.21, P = 0.006; OS: HR = 2.51, 95% CI = 1.52-4.15, P = 0.0038).DNMT3A R882 mutations possessed significant unfavorable prognostic influence on RFS and OS in AML patients.

  10. Increased dosage of the RUNX1/AML1 gene: a third mode of RUNX leukemia?

    PubMed

    Osato, Motomi; Ito, Yoshiaki

    2005-01-01

    RUNX1/AML1, located on chromosome 21, is a key factor in the generation and maintenance of hematopoietic stem cells and the gene most frequently implicated in human leukemias. Chromosome translocations and point mutations are well-documented genetic alterations in RUNX leukemia (also known as CBF leukemia). In addition, overdosage or overexpression of RUNX1 is suspected to be a third mode of RUNX1 involvement in leukemogenesis. The possibility that this mode might underlie Down syndrome-related leukemias caused by trisomy of chromosome 21 is discussed.

  11. MRD in AML: it is time to change the definition of remission.

    PubMed

    Ossenkoppele, Gert J; Schuurhuis, Gerrit Jan

    2014-01-01

    The possibility of defining residual disease far below the morphological level of 5% blast cells is changing the landscape of risk classification in acute myeloid leukemia (AML). The so-called minimal residual disease (MRD) approach at this time can establish the presence of leukemia cells down to levels of 1:1000-1:10(6) white blood cells, compared to 1:20 for morphology. Availability of the newer and more sensitive technology to quantify the level of leukemic burden raises the issue of whether MRD should emerge as a new definition of complete response. This paper explores some of the issues surrounding such a change in definition.

  12. Pressurized grout remote backfilling at AML sites near Beulah and Zap, North Dakota

    SciTech Connect

    Weiner, E.J.; Dodd, W.E.

    1999-07-01

    The Abandoned Mine Lands (AML) Division of the North Dakota Public Service Commission (PSC) is charged with the reclamation of hazardous abandoned mine sites in North Dakota. Several underground lignite coalmines were operated near the cities of Beulah and Zap, North Dakota, from the early 1900's until about 1955. Coal seams in this area were relatively thick and the overburden generally shallow. As these mines have deteriorated with time, deep collapse features, or sinkholes, have surfaced in many areas. These features are very dangerous, especially when they occur at or near residential and commercial areas and public roads. In the past five years, sinkholes have surfaced beneath a commercial building (boat dealership, lounge, and gas station) and beneath a nearby occupied mobile home north of Beulah. sinkholes have also surfaced near KHOL Radio Station in Beulah and in the right of way of a public road south of Zap. The AML Division has conducted several emergency sinkhole-filling projects in these areas. In 1995--97, the AML Division conducted exploratory drilling which confirmed the presence of collapsing underground mines at these sites. The remediation of these sites around Beulah/Zap will take place over several years and involve three or more separate contracts due to budget considerations. In 1997, the AML Division began reclamation at these sties utilizing pressurized grout remote backfilling. In this technique, a cementitious grout is pumped through cased drill holes directly into the mine cavities to fill them and thereby stabilize the surface from collapse. The successful contractor for Phase One of the project was The Concrete Doctor, Inc. (TCDI). This paper will concentrate on Phase One of this work performed from June through September 1997. This project is especially interesting because grout was pumped through holes drilled inside the occupied commercial building. Grout was also pumped through angled holes that intercepted mined workings directly

  13. Targeting the kinase activities of ATR and ATM exhibits therapeutic potential in a mouse model of MLL-rearranged AML

    PubMed Central

    Lafarga, Vanesa; Anton, Marta Elena; Tubbs, Anthony; Chen, Hua Tang; Ergan, Aysegul; Anderson, Rhonda; Bhandoola, Avinash; Pike, Kurt G.; Barlaam, Bernard; Cadogan, Elaine; Wang, Xi; Pierce, Andrew J.; Hubbard, Chad; Armstrong, Scott A.; Nussenzweig, André; Fernandez-Capetillo, Oscar

    2016-01-01

    Among the various subtypes of Acute Myeloid Leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies due to an attenuated response by p53, which induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AMLMLL cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AMLMLL and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AMLMLL mice. Collectively, these data indicated that ATR and ATM inhibition represent potential alternative therapeutic strategies for the treatment of AML, especially MLL-driven leukemias. PMID:27625305

  14. Tunneling nanotube (TNT) formation is downregulated by cytarabine and NF-κB inhibition in acute myeloid leukemia (AML)

    PubMed Central

    Omsland, Maria; Bruserud, Øystein; Gjertsen, Bjørn T; Andresen, Vibeke

    2017-01-01

    Acute myeloid leukemia (AML) is a bone marrow derived blood cancer where intercellular communication in the leukemic bone marrow participates in disease development, progression and chemoresistance. Tunneling nanotubes (TNTs) are intercellular communication structures involved in transport of cellular contents and pathogens, also demonstrated to play a role in both cell death modulation and chemoresistance. Here we investigated the presence of TNTs by live fluorescent microscopy and identified TNT formation between primary AML cells and in AML cell lines. We found that NF-κB activity was involved in TNT regulation and formation. Cytarabine downregulated TNTs and inhibited NF-κB alone and in combination with daunorubicin, providing additional support for involvement of the NF-κB pathway in TNT formation. Interestingly, daunorubicin was found to localize to lysosomes in TNTs connecting AML cells indicating a novel function of TNTs as drug transporting devices. We conclude that TNT communication could reflect important biological features of AML that may be explored in future therapy development. PMID:27974700

  15. Design and kinetic analysis of hammerhead ribozyme and DNAzyme that specifically cleave TEL-AML1 chimeric mRNA

    SciTech Connect

    Choi, Woo-Hyung; Choi, Bo-Ra; Kim, Jae Hyun; Yeo, Woon-Seok; Oh, Sangtaek; Kim, Dong-Eun

    2008-09-12

    In order to develop the oligonucleotides to abolish an expression of TEL-AML1 chimeric RNA, which is a genetic aberration that causes the acute lymphoblastic leukemia (ALL), hammerhead ribozymes and deoxyoligoribozymes that can specifically cleave TEL-AML1 fusion RNA were designed. Constructs of the deoxyribozyme with an asymmetric substrate binding arm (Dz26) and the hammerhead ribozyme with a 4 nt-bulged substrate binding arm in the stem III (buRz28) were able to cleave TEL-AML1 chimeric RNA specifically at sites close to the junction in vitro, without cleaving the normal TEL and AML1 RNA. Single-turnover kinetic analysis under enzyme-excess condition revealed that the buRz28 is superior to the Dz26 in terms of substrate binding and RNA-cleavage. In conjunction with current progress in a gene-delivery technology, the designed oligonucleotides that specifically cleave the TEL-AML1 chimeric mRNA are hoped to be applicable for the treatment of ALL in vivo.

  16. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

    PubMed Central

    Nguyen, Nhu-Y N.; Fong, Chun Yew; Sornkom, Jirawas; Wall, Meaghan; Pavy, Megan; Cullinane, Carleen; Diesch, Jeannine; Devlin, Jennifer R.; Sanij, Elaine; Quin, Jaclyn; Poortinga, Gretchen; Verbrugge, Inge; Baker, Adele; Drygin, Denis; Powell, Jason A.; Johnstone, Ricky W.; Guthridge, Mark A.; Wei, Andrew; McArthur, Grant A.; Pearson, Richard B.

    2017-01-01

    Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs. PMID:28283481

  17. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population.

    PubMed

    Hein, Nadine; Cameron, Donald P; Hannan, Katherine M; Nguyen, Nhu-Y N; Fong, Chun Yew; Sornkom, Jirawas; Wall, Meaghan; Pavy, Megan; Cullinane, Carleen; Diesch, Jeannine; Devlin, Jennifer R; George, Amee J; Sanij, Elaine; Quin, Jaclyn; Poortinga, Gretchen; Verbrugge, Inge; Baker, Adele; Drygin, Denis; Harrison, Simon J; Rozario, James D; Powell, Jason A; Pitson, Stuart M; Zuber, Johannes; Johnstone, Ricky W; Dawson, Mark A; Guthridge, Mark A; Wei, Andrew; McArthur, Grant A; Pearson, Richard B; Hannan, Ross D

    2017-05-25

    Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs. © 2017 by The American Society of Hematology.

  18. Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia.

    PubMed

    Yotnda, P; Garcia, F; Peuchmaur, M; Grandchamp, B; Duval, M; Lemonnier, F; Vilmer, E; Langlade-Demoyen, P

    1998-07-15

    Cytotoxic T lymphocytes (CTL) are potent effector cells that could provide long term antitumor immunity if induced by appropriate vaccines. CTL recognize 8-14 amino acid-long peptides processed intracellularly and presented by MHC class I molecules. A well-characterized example of a potential tumor antigen in childhood pre-B Acute Lymphoblastic Leukemia (ALL) results from the chromosomal translocation 12;21 leading to the fusion of the ETV6 and AML1 genes. This translocation is observed in > 25% of ALL-patients. In this study, we have examined whether the chimeric ETV6-AML1 protein could serve as a tumor specific antigen for CTL in HLA-A2.1 individuals. We have identified a nonapeptide (RIAECILGM), encoded by the fusion region of the ETV6-AML1 protein, that binds to HLA-A2.1 molecules and induces specific primary CTL in peripheral blood lymphocytes from healthy donors. These CTL specifically lysed HLA-A2.1 tumor cells endogeneously expressing the ETV6-AML fusion protein. CTL with similar functional capacities were found with high frequencies and cloned from one patient's bone marrow indicating that ETV6-AML1-specific anti-ALL CTL are, at least in some patients, spontaneously stimulated and might participate to host antileukemia defense.

  19. Effects of TLR agonists on maturation and function of 3-day dendritic cells from AML patients in complete remission

    PubMed Central

    2011-01-01

    Background Active dendritic cell (DC) immunization protocols are rapidly gaining interest as therapeutic options in patients with acute myeloid leukemia (AML). Here we present for the first time a GMP-compliant 3-day protocol for generation of monocyte-derived DCs using different synthetic Toll-like receptor (TLR) agonists in intensively pretreated patients with AML. Methods Four different maturation cocktails were compared for their impact on cell recovery, phenotype, cytokine secretion, migration, and lymphocyte activation in 20 AML patients and 25 healthy controls. Results Maturation cocktails containing the TLR7/8 agonists R848 or CL075, with and without the addition of the TLR3 agonist poly(I:C), induced DCs that had a positive costimulatory profile, secreted high levels of IL-12(p70), showed chemotaxis to CCR7 ligands, had the ability to activate NK cells, and efficiently stimulated antigen-specific CD8+ T cells. Conclusions Our results demonstrate that this approach translates into biologically improved DCs, not only in healthy controls but also in AML patients. This data supports the clinical application of TLR-matured DCs in patients with AML for activation of innate and adaptive immune responses. PMID:21910911

  20. Comparative proteomic analysis of human leukemic cells with and without inducible expression of leukemogenic AML1-ETO protein.

    PubMed

    Zhang, Lei; Wang, Li-Shun; Xu, Ying; Xia, Li; Chen, Wen-Li; Zheng, Ying; Chen, Guo-Qiang

    2006-08-31

    AML1-ETO is a leukemogenic fusion protein generated by chromosomal translocation t(8; 21) (q22; q22), one of the most frequent chromosomal abnormalities in acute myeloid leukemia. The fusion protein has been shown to present dichotomous functions on leukemic cells: growth arrest versus differentiation block. However, their precise molecular mechanisms are not completely clear. In this work, we try to explore potential AML1-ETO-targeted proteins through comparing two-dimensional electrophoresis (2DE)-based global protein expression profiles of leukemic U937 cells with and without inducible expression of AML1-ETO. As a result, we identified 14 unique proteins deregulated in AML1-ETO-carrying leukemic cells, including 3 up-regulated such as hairy and enhancer of split 5 (HES5) and 11 down-regulated such as MAT1 (menage a trois-1) and mitogen-activated protein kinase organizer 1 (MORG1). These proteins were widely involved in stem cell maintenance, cell cycle, signal transduction and transcription. The further investigation on their roles in leukemic cells will uncover new clues to understanding leukemogenic effects of AML1-ETO fusion protein.

  1. Normal bone marrow signal-transduction profiles: a requisite for enhanced detection of signaling dysregulations in AML

    PubMed Central

    Marvin, James; Swaminathan, Suchitra; Kraker, Geoffrey; Chadburn, Amy; Jacobberger, James

    2011-01-01

    Molecular and cytogenetic alterations are involved in virtually every facet of acute myeloid leukemia (AML), including dysregulation of major signal-transduction pathways. The present study examines 5 phosphoproteins (pErk, pAkt, pS6, pStat3, and pStat5) in response to 5 cytokine/growth factors (stem cell factor [SCF], Flt-3/Flk-2 ligand [FL], granulocyte/macrophage-colony stimulating factor [GM-CSF], interleukin-3 [IL-3], and granulocyte-CSF [G-CSF]) within 7 immunophenotypically defined populations, spanning progenitor to mature myeloid/myelomonocytic cells in normal bone marrows with further comparison to AML samples. The normal cohort showed pathway-specific responses related to lineage, maturation, and stimulus. Heterogeneous-signaling responses were seen in homogeneous immunophenotypic subsets emphasizing the additive information of signaling. These profiles provided a critical baseline for detection of dysregulated signaling in AML falling into 4 broad categories, viz lack of response, increased activation, altered constitutive expression, and dysregulated response kinetics, easily identified in 10 of 12 AMLs. These studies clearly show robust and reproducible flow cytometry phosphoprotein analyses capable of detecting abnormal signal-transduction responses in AML potentially contributing to definitive reliable identification of abnormal cells. As functional correlates of underlying genetic abnormalities, signal-transduction abnormalities may provide more stable indicators of abnormal cells than immunophenotyping which frequently changes after therapy and disease recurrence. PMID:21233314

  2. CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900

    PubMed Central

    Gönen, Mithat; Sun, Zhuoxin; Figueroa, Maria E.; Patel, Jay P.; Abdel-Wahab, Omar; Racevskis, Janis; Ketterling, Rhett P.; Fernandez, Hugo; Rowe, Jacob M.; Tallman, Martin S.; Melnick, Ari; Levine, Ross L.

    2012-01-01

    We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group trial, E1900. We identified CD25POS myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25POS patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25NEG cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITDPOS AML was restricted to CD25POS patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25POS status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25POS status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML. PMID:22855599

  3. Pre-transplant MRD predicts outcome following reduced-intensity and myeloablative allogeneic hemopoietic SCT in AML.

    PubMed

    Anthias, C; Dignan, F L; Morilla, R; Morilla, A; Ethell, M E; Potter, M N; Shaw, B E

    2014-05-01

    The presence of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) has been associated with adverse outcomes in AML patients treated with chemotherapy alone, but its impact in the setting of allogeneic hematopoietic SCT (HSCT) is less clear. We studied 88 patients who underwent myeloablative (MA) or reduced-intensity conditioned allogeneic HSCT for AML in first or subsequent remission at our center. MRD status was determined using three-color MFC on pre-HSCT BM aspirates, and patients were stratified by MRD status into MRD-negative, low-level MRD-positive (<1%) or high-level MRD-positive groups (1-4.9%). Two-year survival estimates in these groups were 66.8%, 51% and 30%, respectively (P=0.012), and 2-year estimates of relapse were 7.6, 37 and 70% (P<0.001). Pre-HSCT MRD was related to disease characteristics including secondary AML (P=0.002) and primary induction failure (P=0.005), but, despite these strong correlations, MRD remained independently associated with poorer survival in multivariate analysis (hazard ratio, 1.92; P=0.014). Pre-HSCT MRD is associated with adverse clinical outcomes in AML patients undergoing reduced-intensity or MA HSCT in first or subsequent remission and should be integrated into transplant strategies for patients with AML.

  4. MIT LMFBR blanket research project. Final summary report

    SciTech Connect

    Driscoll, M.J.

    1983-08-01

    This is a final summary report on an experimental and analytical program for the investigation of LMFBR blanket characteristics carried out at MIT in the period 1969 to 1983. During this span of time, work was carried out on a wide range of subtasks, ranging from neutronic and photonic measurements in mockups of blankets using the Blanket Test Facility at the MIT Research Reactor, to analytic/numerical investigations of blanket design and economics. The main function of this report is to serve as a resource document which will permit ready reference to the more detailed topical reports and theses issued over the years on the various aspects of project activities. In addition, one aspect of work completed during the final year of the project, on doubly-heterogeneous blanket configurations, is documented for the record.

  5. MIT-Skywalker: Evaluating comfort of bicycle/saddle seat.

    PubMed

    Goncalves, Rogerio S; Hamilton, Taya; Daher, Ali R; Hirai, Hiroaki; Krebs, Hermano I

    2017-07-01

    The MIT-Skywalker is a robotic device developed for the rehabilitation of gait and balance after a neurological injury. This device has been designed based on the concept of a passive walker and provides three distinct training modes: discrete movement, rhythmic movement, and balance training. In this paper, we present our efforts to evaluate the comfort of a bicycle/saddle seat design for the system's novel actuated body weight support device. We employed different bicycle and saddle seats and evaluated comfort using objective and subjective measures. Here we will summarize the results obtained from a study of fifteen healthy subjects and one stroke patient that led to the selection of a saddle seat design for the MIT-Skywalker.

  6. The Harvard-MIT PHD Program in Bioastronautics

    NASA Astrophysics Data System (ADS)

    Young, Laurence R.; Natapoff, Alan

    2008-06-01

    The National Space Biomedical Research Institute (NSBRI)1 supports a PhD program in Space Life Sciences with a specialty in Bioastronautics at MIT. (A sibling program operates at TAMU.) It gives broad training in life sciences, emphasizes hands-on field experience, provides access to laboratories in the Harvard-MIT community for thesis research, and prepares students for many options in space biomedicine. The Program trains prospective leaders in the field able to manage the challenges of design for the life-hostile space environment. Beyond subject and thesis work, students participate in a summer internship and a clinical preceptorship at a NASA center--and an introduction to clinical medicine and medical engineering.

  7. In vitro generation of tumor specific T cells that recognize a shared antigen of AML: molecular characterization of TCR genes.

    PubMed

    Coppage, Myra; Belanger, Todd; Zauderer, Maurice; Sahasrabudhe, Deepak

    2007-02-01

    The identification of immunologically relevant tumor antigens is hampered by the difficulty of generating tumor-specific cytotoxic T cells (CTL). We present data demonstrating in vitro induction of autologous acute myelogenous leukemia (AML)-specific CTL. The specific T cell receptor has been identified and cloned. The CTL demonstrated specific lysis to autologous tumor blasts, but not to autologous BLCL or the NK-sensitive target K562. The clone secreted GM-CSF, TNFa, and IFNg when stimulated with AML blasts from 3 of 11 patients or cell lines tested, but not with K562 or autologous B-LCL. These three AML samples share a single HLA Class I antigen, HLA-A24. The T cell receptor genes identified by molecular methods are Vbeta7.9-J2.3-Cbeta2 and Valpha17-J49-Calpha.

  8. [Features of Immunophenotypes and Characteristics of Molecular Biology and Cellular Genetics of AML Patients with CD4 and CD7 Expression].

    PubMed

    Liu, Tie-Qiang; Huang, Shan; Yao, Bo; Liu, Zhi-Qing; Yu, Chang-Lin; Qiao, Jian-Hui; Sun, Qi-Yun; Hu, Kai-Xun; Huang, Ya-Jing; Zhang, Rui; Li, Yu-Fang; Bai, Juan; Sun, Yu-Jing; Li, Bing-Xia; Wang, Dong-Mei; Wang, Yi; Guo, Mei

    2016-12-01

    To explore the features of immunophenotypes and the characteristics of molecular biology and cellular genetics of AML patients with CD7 and CD4 expression. The immunophenotypical markers of AML cells were detected by multiple parameter flow cytometry; the expression of WT1, MDK, ETO, PML-RaRa and BCR-ABL were detected by RT-PCR; and cellular features were analyzed by R-band in 304 patients. The patients were divided into three groups according to their immunophenotypes: AML with CD7 expression (CD7 group), AML with CD4 expression(CD4 group) and AML without CD7 and CD4 expression (common AML group). The expression rate and level of HLA-DR in CD7 group were higher than those in the common AML group, and the expression rate of CD33 and CD34 was higher than that in the other two groups. The expression rate and level of CD15, CD64 in the CD4 group were higher than those in the other 2 groups, and the expression rate and level of CD33 were higher than those in the common AML group. WT1 expression in the CD7 group was lower than that in the common AML group. PML-RaRa was not detected in the CD7 group. AML with co-expression of CD4 or CD7 showed more normal karyotype. (15;17) was not found in AML with CD7 expression. AML cells with CD7 expression originate from precursor cells and are blocked in the early phase of hematological development; AML cells with CD4 expression originate from more mature stage of hematological devevelopment and with CD33, CD64 and CD15 high expression; AML cells with CD7 and CD4 expression are characterized by no-specific change of cellular genetics. According to the expression level and intesity of CD4 and CD7, and together with other specific lineage markers, the MRD in AML patients can be quantitatively detected.

  9. miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target

    PubMed Central

    Yamamoto, Haruna; Lu, Jun; Oba, Shigeyoshi; Kawamata, Toyotaka; Yoshimi, Akihide; Kurosaki, Natsumi; Yokoyama, Kazuaki; Matsushita, Hiromichi; Kurokawa, Mineo; Tojo, Arinobu; Ando, Kiyoshi; Morishita, Kazuhiro; Katagiri, Koko; Kotani, Ai

    2016-01-01

    The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor prognostic leukemia. PMID:26754824

  10. Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML.

    PubMed

    Ustun, C; Wiseman, A C; Defor, T E; Yohe, S; Linden, M A; Oran, B; Burke, M; Warlick, E; Miller, J S; Weisdorf, D

    2013-11-01

    Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients with AML in CR. However, relapse after RIC allo-HCT may indicate heterogeneity in the stringency of CR. Strict definition of CR requires no evidence of leukemia by both morphologic and flow cytometric criteria. We re-evaluated 85 AML patients receiving RIC allo-HCT in CR to test if a strict definition of CR had direct implications for the outcome. These patients had leukemia immunophenotype documented at diagnosis and analyzed at allo-HCT. Eight (9.4%) had persistent leukemia by flow cytometric criteria at allo-HCT. The patients with immunophenotypic persistent leukemia had a significantly increased relapse (hazard ratio (HR): 3.7; 95% confidence interval (CI): 1.3-10.3, P=0.01) and decreased survival (HR: 2.9; 95% CI: 1.3-6.4, P<0.01) versus 77 patients in CR by both morphology and flow cytometry. However, the pre-allo-HCT bone marrow (BM) blast count (that is, 0-4%) was not significantly associated with risks of relapse or survival. These data indicate the presence of leukemic cells, but not the BM blast count affects survival. A strict morphologic and clinical lab flow cytometric definition of CR predicts outcomes after RIC allo-HCT, and therefore is critical to achieve at transplantation.

  11. Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis

    PubMed Central

    Levine, Jacob H.; Simonds, Erin F.; Bendall, Sean C.; Davis, Kara L.; Amir, El-ad D.; Tadmor, Michelle; Litvin, Oren; Fienberg, Harris; Jager, Astraea; Zunder, Eli; Finck, Rachel; Gedman, Amanda L.; Radtke, Ina; Downing, James R.; Pe’er, Dana; Nolan, Garry P.

    2015-01-01

    SUMMARY Acute myeloid leukemia (AML) manifests as phenotypically and functionally diverse cells, often within the same patient. Intratumor phenotypic and functional heterogeneity have been linked primarily by physical sorting experiments, which assume that functionally distinct subpopulations can be prospectively isolated by surface phenotypes. This assumption has proven problematic and we therefore developed a data-driven approach. Using mass cytometry, we profiled surface and intracellular signaling proteins simultaneously in millions of healthy and leukemic cells. We developed PhenoGraph, which algorithmically defines phenotypes in high-dimensional single-cell data. PhenoGraph revealed that the surface phenotypes of leukemic blasts do not necessarily reflect their intracellular state. Using hematopoietic progenitors, we defined a signaling-based measure of cellular phenotype, which led to isolation of a gene expression signature that was predictive of survival in independent cohorts. This study presents new methods for large-scale analysis of single-cell heterogeneity and demonstrates their utility, yielding insights into AML pathophysiology. PMID:26095251

  12. Frontline therapy of AML: should the older patient be treated differently?

    PubMed

    Foran, James M

    2014-06-01

    Optimal treatment of acute myeloid leukemia (AML) in older adults (age ≥60 years) remains largely undefined, in part because of the inadequate response to available therapies, the poor prognosis relative to younger adults, the heterogeneity of the population, and the difficulty in determining who is fit for intensive therapy. In contrast to younger patients, there remains uncertainty about disease biology and molecular prognostic factors in elderly AML. While almost all patients may benefit from treatment, with the exception of reduced intensity allogeneic transplantation, there is little evidence that further intensifying therapy will improve outcomes. In fact, recent studies suggest that de-intensified treatment may in fact be superior and allow access to therapy for more patients. Both the disease and the patient must be approached holistically in order to make the best frontline treatment choice together. It is critical that we support well-designed clinical trials to develop more effective frontline therapies, develop more informative biomarkers, and to better understand who is a candidate for curative treatment.

  13. Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus

    PubMed Central

    Brandwein, Joseph M; Geddes, Michelle; Kassis, Jeannine; Kew, Andrea K; Leber, Brian; Nevill, Thomas; Sabloff, Mitchell; Sandhu, Irwindeep; Schuh, Andre C; Storring, John M; Ashkenas, John

    2013-01-01

    Patients over age 60 comprise the majority of those diagnosed with acute myeloid leukemia (AML), but treatment approaches in this population are variable, with many uncertainties and controversies. Our group conducted a literature review to summarize the latest information and to develop a consensus document with practical treatment recommendations. We addressed five key questions: selection criteria for patients to receive intensive induction chemotherapy; optimal induction and post-remission regimens; allogeneic hematopoietic stem cell transplantation (HSCT); treatment of patients not suitable for induction chemotherapy; and treatment of patients with prior hematological disorders or therapy-related AML. Relevant literature was identified through a PubMed search of publications from 1991 to 2012. Key findings included the recognition that cytogenetics and molecular markers are major biologic determinants of treatment outcomes in the older population, both during induction therapy and following HSCT. Although disease-specific and patient-specific risk factors for poor outcomes are more common in the older population, age is not in itself sufficient grounds for withholding established treatments, including induction and consolidation chemotherapy. The role of HSCT and use of hypomethylating agents are discussed. Finally, suggested treatment algorithms are outlined, based on these recommendations. PMID:23675565

  14. Polymorphisms in DNA repair genes and therapeutic outcomes of AML patients from SWOG clinical trials.

    PubMed

    Kuptsova, Nataliya; Kopecky, Kenneth J; Godwin, John; Anderson, Jeanne; Hoque, Ashraful; Willman, Cheryl L; Slovak, Marilyn L; Ambrosone, Christine B

    2007-05-01

    Repair of damage to DNA resulting from chemotherapy may influence drug toxicity and survival in response to treatment. We evaluated the role of polymorphisms in DNA repair genes APE1, XRCC1, ERCC1, XPD, and XRCC3 in predicting therapeutic outcomes of older adults with acute myeloid leukemia (AML) from 2 Southwest Oncology Group (SWOG) clinical trials. All patients received standard chemotherapy induction regimens. Using logistic and proportional hazards regression models, relationships between genotypes, haplotypes, and toxicities, response to induction therapy, and overall survival were evaluated. Patients with XPD Gln751C/Asp312G ('D') haplotype were more likely to have complete response (OR = 3.06; 95% CI, 1.44-6.70) and less likely to have resistant disease (OR = 0.32; 95%CI, 0.14-0.72) than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung (P = .037) and metabolic (P = .041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (OR = 0.32; 95%CI, 0.11-0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. These data from clinical trials of older patients treated for AML indicate that variants in DNA repair pathways may have an impact on both outcomes of patients and toxicities associated with treatments. With validation of results in larger samples, these findings could lead to optimizing individual chemotherapy options.

  15. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient.

  16. Autologous bone marrow transplantation for children with AML in first remission.

    PubMed

    Neudorf, S; Sanders, J; Kobrinsky, N; Alonzo, T A; Buxton, A; Buckley, J D; Howells, W; Gold, S; Barnard, D R; DeSwarte, J; Kalousek, D; Lange, B J; Woods, W G

    2007-08-01

    In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT. Myeloid and platelet engraftment occurred at a median of 44 and 42 days, respectively. Disease-free survival (DFS), relapse-free survival and overall survival at 8 years post induction were 47% (95% confidence interval (CI): 38-55), 50% (CI: 42-59) and 55% (CI: 46-63), respectively. Multivariate analysis of DFS showed WBC <50 000/microl and having received intensively timed induction therapy were associated with improved DFS. Recipients who received intensive timed induction therapy and whose WBC was less than 50 000/microl had a DFS at 8 years of 62% (CI: 49-73). Conversely, recipients who received intensive timed induction therapy patients whose WBC was > or =50 000/microl had a DFS of 33% (CI: 17-50), P=0.003. The results confirm previous studies that ABMT is effective post remission therapy for pediatric patients with AML in first remission.

  17. Peripheral Blood WT1 Expression Predicts Relapse in AML Patients Undergoing Allogeneic Stem Cell Transplantation

    PubMed Central

    Malagola, Michele; Skert, Cristina; Ruggeri, Giuseppina; Ribolla, Rossella; Bernardi, Simona; Borlenghi, Erika; Pagani, Chiara; Rossi, Giuseppe; Caimi, Luigi; Russo, Domenico

    2014-01-01

    To evaluate if WT1 expression may predict relapse after allo-SCT, we analyzed WT1 levels on peripheral blood (PB) and bone marrow (BM) before and after allo-SCT in 24 AML patients with WT1 overexpression at diagnosis. Five copies of WT1/ABL × 104 from PB were identified as the threshold value that correlated with relapse after allo-SCT. The same correlation was not identified when WT1 expression was assessed from bone marrow (BM). Eight out of 11 (73%) patients with a pre-allo-SCT PB-WT1 ≥ 5 and 4/13 (31%) patients with a pre-allo-SCT PB-WT1 < 5 relapsed, respectively (P = 0.04). The incidence of relapse was higher in patients with PB-WT1 ≥ 5 measured after allo-SCT, at the 3rd (56% versus 38%; P = 0.43) and at the 6th month (71% versus 20%; P = 0.03). Patients with pretransplant PB-WT1 < 5 had significantly better 2-year OS and LFS than patients with a PB-WT1 ≥ 5 (81% versus 0% and 63% versus 20%) (P = 0.02). Our data suggest the usefulness of WT1 monitoring from PB to predict the relapse in allotransplanted AML patients and to modulate the intensity of conditioning and/or the posttransplant immunosuppression in an attempt to reduce the posttransplant relapse risk. PMID:25202702

  18. The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML

    PubMed Central

    Heidel, Florian H.; Bullinger, Lars; Arreba-Tutusaus, Patricia; Wang, Zhu; Gaebel, Julia; Hirt, Carsten; Niederwieser, Dietger; Lane, Steven W.; Döhner, Konstanze; Vasioukhin, Valera; Fischer, Thomas

    2013-01-01

    A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1−/− HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML. PMID:23277453

  19. Astronomen bei der Arbeit - Live-Konferenz mit La Palma

    NASA Astrophysics Data System (ADS)

    Beck, Paul G.

    2012-02-01

    "Wie kann man sich die nächtliche Arbeit eines Astronomen am Teleskop vorstellen?" Diese Frage stellen sich viele wissenschaftlich interessierte Menschen, die noch kein professionelles Observatorium besuchen konnten. Das multimediale Experiment "Call a Scientist" verband Besucher einer österreichischen Amateursternwarte live mit dem Großobservatorium in La Palma und brachte damit einer interessierten Öffentlichkeit seltene Einblicke in die Arbeitsweise der modernen Astronomie nahe.

  20. MIT Laboratory for Computer Science Progress Report 27

    DTIC Science & Technology

    1990-06-01

    plications to computer graphics and database retrieval systems. The survey paper identifies three general methods for range queries in computational geometry ...Massachusetts Laboratory for Institute of Computer Science Technology Progress Report July 1989- 27 a) June 1990 00 N Nv NOV C510D The work reported ...Arlington, VA 22217 11. TITLE (Include Security Clasvfication) MIT Laboratory for Computer Science Progress Report - 27 12. PERSONAL AUTHOR(S) M.L

  1. AML1/ETO promotes the maintenance of early hematopoietic progenitors in NOD/SCID mice but does not abrogate their lineage specific differentiation.

    PubMed

    Bäsecke, Jörg; Schwieger, Maike; Griesinger, Frank; Schiedlmeier, Bernd; Wulf, Gerald; Trümper, Lorenz; Stocking, Carol

    2005-02-01

    AML1-ETO is generated by the t(8;21) translocation found in approximately 12% of acute myelogenous leukemia. Studies to delineate the mechanism by which AML1-ETO induces leukemia have primarily relied on transformed human cell lines or murine model systems. The goal of this study was to determine the effect of AML1-ETO expression on primary human hematopoietic cells in vitro and in a xenograft model. We used a FMEV retroviral vector for the transfer of AML1/ETO into human CD34 + cells. The repopulation, self-renewal, and differentiation potential of infected cells were assessed in serum-free liquid culture, colony assays, and in transplanted NOD-SCID mice. High transcription levels were confirmed by real-time PCR. AML1-ETO expressing cells were expandable for up to 12 weeks and retained an immature morphology. The capacity for prolonged survival, however, did not abrogate maturation, as AML1-ETO cells gave rise to normal colonies in a CFU-assay. AML1/ETO-expressing cells also contributed to myeloid (CD15, CD33), B-lymphoid (CD20), NK-cell (CD56) and erythroid (GPA) lineages in xenografted NOD/SCID mice. Although able to engraft all major lineages, AML1/ETO transplanted cells were primarily found in less differentiated fractions as measured by cell surface markers CD34 and CD38. In spite of a good engraftment and prolonged observation period none of the NOD/SCID-mice developed an acute myelogenous leukemia. Our findings demonstrate that AML1/ETO promotes the maintenance of early human hematopoietic progenitors, but does not abrogate their physiologic differentiation. Furthermore, the leukemogenic potential of AML1/ETO expressed in human progenitors is low, despite transcription levels equivalent to those found in AMLs.

  2. Topologie und Dynamische Netzwerke: Anwendungen Der Optimierung MIT Zukunft

    NASA Astrophysics Data System (ADS)

    Leugering, Günter; Martin, Alexander; Stingl, Michael

    Die optimale Auslegung von Infrastrukturen z. B. bei der Verkehrsplanung und bei der Planung von Versorgungssystemen, die optimale Strukturierung bzw. Formgebung von Materialien und Werkstücken z. B. im Leichtbau sind aktuelle Themen angewandter Forschung. In beiden Bereichen wurde bis in die jüngste Zeit vornehmlich eine simulationsbasierte Optimierung auf der Grundlage einer Parameterjustierung vorgenommen, die oft wenig systematisch und zeit- und kostenintensiv ist. Stattdessen erweisen sich modellbasierte mathematische Optimierungsalgorithmen zusammen mit moderner numerischer Simulations-und Visualisierungstechnologie zunehmend als Katalysator neuer Technologien. Eine so verstandene Mathematische Optimierung kann bereits auf beeindruckende Erfolgsgeschichten verweisen und so den Anspruch als eine Zukunftsdisziplin behaupten. Diesem Anspruch trägt die Einrichtung des DFG-Schwerpunktprogramms 1253, Optimierung mit partiellen Differentialgleichungen’ im Jahre 2006 Rechnung, in dem über 25 Projekte im Bundesgebiet sowohl auf die theoretische Fundierung, als auch und insbesondere auf die Verzahnung zwischen Methodenentwicklung und numerischer Realisierung fokussieren. Forschung im Bereich der mathematischen Optimierung und Steuerung von Prozessen bzw. Eigenschaften, die mit Hilfe partieller Differentialgleichungen, so genannten, verteilten Systemen’, beschrieben werden, erfolgt im Kontext konkreter und exemplarischer Anwendungssituationen, die neue mathematische Herausforderungen markieren: Sicherheitsvorgaben etwa bei der Belastung von Gas- und Frischwasserleitungen oder solche für die Belastbarkeit von Verkehrsflugzeugen führen auf Druckbeschränkungen bzw.

  3. New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins

    PubMed Central

    Li, Jian; Guo, Chun; Steinauer, Nickolas; Zhang, Jinsong

    2016-01-01

    BACKGROUND Nearly 15% of acute myeloid leukemia (AML) cases are caused by aberrant expression of AML1-ETO, a fusion protein generated by the t(8;21) chromosomal translocation. Since its discovery, AML1-ETO has served as a prototype to understand how leukemia fusion proteins deregulate transcription to promote leukemogenesis. Another leukemia fusion protein, E2A-Pbx1, generated by the t(1;19) translocation, is involved in acute lymphoblastic leukemias (ALLs). While AML1-ETO and E2A-Pbx1 are structurally unrelated fusion proteins, we have recently shown that a common axis, the ETO/E-protein interaction, is involved in the regulation of both fusion proteins, underscoring the importance of studying protein–protein interactions in elucidating the mechanisms of leukemia fusion proteins. OBJECTIVE In this review, we aim to summarize these new developments while also providing a historic overview of the related early studies. METHODS A total of 218 publications were reviewed in this article, a majority of which were published after 2004.We also downloaded 3D structures of AML1-ETO domains from Protein Data Bank and provided a systematic summary of their structures. RESULTS By reviewing the literature, we summarized early and recent findings on AML1-ETO, including its protein–protein interactions, transcriptional and leukemogenic mechanisms, as well as the recently reported involvement of ETO family corepressors in regulating the function of E2A-Pbx1. CONCLUSION While the recent development in genomic and structural studies has clearly demonstrated that the fusion proteins function by directly regulating transcription, a further understanding of the underlying mechanisms, including crosstalk with other transcription factors and cofactors, and the protein–protein interactions in the context of native proteins, may be necessary for the development of highly targeted drugs for leukemia therapy. PMID:28261265

  4. Cellular Intrinsic Mechanism Affecting the Outcome of AML Treated with Ara-C in a Syngeneic Mouse Model

    PubMed Central

    Tan, Dongming; Su, Guangsong; Zheng, Yanwen; He, Chao; Mao, Zhengwei J.; Singleton, Timothy P.; Yin, Bin

    2014-01-01

    The mechanisms underlying acute myeloid leukemia (AML) treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. PMID:25314317

  5. Phylogenetic relationships of the Gomphales based on nuc-25S-rDNA, mit-12S-rDNA, and mit-atp6-DNA combined sequences

    Treesearch

    Admir J. Giachini; Kentaro Hosaka; Eduardo Nouhra; Joseph Spatafora; James M. Trappe

    2010-01-01

    Phylogenetic relationships among Geastrales, Gomphales, Hysterangiales, and Phallales were estimated via combined sequences: nuclear large subunit ribosomal DNA (nuc-25S-rDNA), mitochondrial small subunit ribosomal DNA (mit-12S-rDNA), and mitochondrial atp6 DNA (mit-atp6-DNA). Eighty-one taxa comprising 19 genera and 58 species...

  6. Azelainsäure 20 % Creme: Auswirkung auf Lebensqualität und Krankheitsaktivität bei erwachsenen Patientinnen mit Acne vulgaris.

    PubMed

    Kainz, Julius Thomas; Berghammer, Gabriele; Auer-Grumbach, Piet; Lackner, Verena; Perl-Convalexius, Sylvia; Popa, Rodica; Wolfesberger, Barbara

    2016-12-01

    Zur Wirksamkeit von Aknetherapien und deren Auswirkungen auf die Lebensqualität erwachsener Patienten liegen kaum Daten vor. ZIEL: Erhebung der Wirkung von Azelainsäure 20 % Creme (Skinoren(®) ) auf Akne-Schweregrad und krankheitsbedingte Lebensqualität. Nichtinterventionelle Studie bei erwachsenen Patientinnen mit leichter bis mittelschwerer Akne. Wirksamkeitsparameter waren DLQI sowie Akne-Schweregrad im Gesicht, am Dekolleté sowie am Rücken im Gesamturteil des Prüfarztes (IGA-Skala: Grad 1 = annähernd reine Haut; 2 = leichte Akne; 3 = mittelschwere Akne). Visiten waren zu Studienbeginn sowie nach 4-8 und zwölf Wochen geplant. Von den 251 eingeschlossenen Patientinnen lag zu Studienbeginn bei 59 %, 31 % bzw. 10 % ein IGA-Grad von 1, 2 bzw. 3 vor; die am häufigsten betroffene Hautpartie war das Gesicht (IGA-Grad 2 oder 3: 79 %). Nach zwölf Behandlungswochen war eine signifikante Besserung der Acne vulgaris im Gesicht (IGA-Grad 0 oder 1: 82 %) sowie auf Dekolleté und Rücken feststellbar. Der mediane DLQI-Wert sank von neun zu Studienbeginn auf fünf nach zwölf Behandlungswochen. Neunzig Prozent der behandelnden Ärzte und Patientinnen beurteilten die Verträglichkeit der Behandlung als sehr gut oder gut. Die Anwendung von 20%iger Azelainsäure-Creme führt bei erwachsenen Frauen zu einer signifikanten Besserung der Acne vulgaris und der krankheitsbedingten Lebensqualität. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  7. Successful management of pulmonary hemorrhage and aspergillosis in a patient with acute myeloid leukemia (AML-M3)

    PubMed Central

    Gunbatar, Hulya; Demir, Cengiz; Kara, Erdal; Esen, Ramazan; Sertogullarindan, Bunyamin; Asker, Selvi

    2015-01-01

    A 35-year-old man presented with a one month history of gingival bleeding. He was diagnosed with Acute Myeloid Leukemia (AML-M3). During treatment he developed alveolar hemorrhage for which he was treated with a steroid. After the steroid treatment he developed a nodule, a cavitary lesion and atelectasia in the left lung. He was treated with voriconazole. After therapy with voriconazole his lesion significantly decreased. This case illustrates the efficacy and safety of antifungal therapy with voriconazole for aspergillosis complicated by AML. PMID:26744658

  8. Successful management of pulmonary hemorrhage and aspergillosis in a patient with acute myeloid leukemia (AML-M3).

    PubMed

    Gunbatar, Hulya; Demir, Cengiz; Kara, Erdal; Esen, Ramazan; Sertogullarindan, Bunyamin; Asker, Selvi

    2015-01-01

    A 35-year-old man presented with a one month history of gingival bleeding. He was diagnosed with Acute Myeloid Leukemia (AML-M3). During treatment he developed alveolar hemorrhage for which he was treated with a steroid. After the steroid treatment he developed a nodule, a cavitary lesion and atelectasia in the left lung. He was treated with voriconazole. After therapy with voriconazole his lesion significantly decreased. This case illustrates the efficacy and safety of antifungal therapy with voriconazole for aspergillosis complicated by AML.

  9. Changes in the MALT1-A20-NF-κB expression pattern may be related to T cell dysfunction in AML.

    PubMed

    Shi, Li; Chen, Shaohua; Lu, Yuhong; Wang, Xu; Xu, Ling; Zhang, Fan; Yang, Lijian; Wu, Xiuli; Li, Bo; Li, Yangqiu

    2013-04-30

    To elucidate the characteristics of T-cell receptor (TCR) signal transduction in T-cells from acute myeloid leukemia (AML), the mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1), A20, NF-κB and MALT1-V1 gene expression levels in CD3+ T cells sorted from the peripheral blood of patients with AML were analyzed by real-time PCR. A significantly lower MALT1 and A20 expression level was found in T cells from patients with AML compared with healthy controls (p = 0.045, p < 0.0001); however, the expression level of MALT1-V1 (variant 1) was significantly higher in the AML group than in the healthy control group (p = 0.006), and the expression level of NF-κB was increased in the AML group. In conclusion, the characteristics of the expression pattern of MALT1-A20-NF-κB and the distribution of MALT1 variants in T cells from AML were first characterized. Overall, low TCR-CD3 signaling is related to low MALT1 expression, which may related to T cell immunodeficiency, while the up-regulation of MALT1-V1 may play a role in overcoming the T cell activity by downregulating A20 in patients with AML, which may be related to a specific response to AML-associated antigens.

  10. Establishment of xenotransplantation model of human CN-AML with FLT3-ITD (mut) /NPM1 (-) in NOD/SCID mice.

    PubMed

    Shang, Zhen; Wang, Jue; Wang, Di; Xiao, Min; Li, Tong-juan; Wang, Na; Huang, Liang; Zhou, Jian-feng

    2013-06-01

    Patients with FLT3-ITD (mut) /NPM1 (-) cytogenetically normal acute myeloid leukemia (CN-AML), as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is beneficial to generate xenotransplantation model of FLT3-ITD (mut) /NPM1 (-) CN-AML to better understand the pathogenesis and therapeutic strategies of such AML subtype. The purpose of present study was to establish the xenotransplantation model in NOD/SCID mice with FLT3-ITD (mut) /NPM1 (-) CN-AML primary cells. The FLT3-ITD (mut) /NPM1 (-) CN-AML primary cells from 3 of 7 cases were successfully transplanted into NOD/SCID mice, and human CD45 positive cells were detected in the peripheral blood, spleen and bone marrow of mice by using flow cytometry. Infiltration of human leukemia cells in various organs of mice was observed by using immunohistochemistry. Gene analysis confirmed sustained FLT3/ITD mutation without NPM1 mutation in mice. By performing serial transplantation, it was found that characteristics of the leukemia cells in secondary and tertiary generation models remained unchanged. Moreover, in vivo cytarabine administration could extend survival of NOD/SCID mice, which was consistent with clinical observation. In conclusion, we successfully established xenotransplantation model of human FLT3-ITD (mut) /NPM1 (-) CN-AML in NOD/SCID mice. The model was able to present primary disease and suitable to evaluate the curative effects of new drugs or therapy strategies.

  11. Apoptosis repressor with caspase recruitment domain is regulated by MAPK/PI3K and confers drug resistance and survival advantage to AML

    PubMed Central

    Mak, P. Y.; Mak, D. H.; Mu, H.; Shi, Y.; Ruvolo, P.; Ruvolo, V.; Jacamo, R.; Burks, J. K.; Wei, W.; Huang, X.; Kornblau, S. M.; Andreeff, M.; Carter, B. Z.

    2014-01-01

    The apoptosis repressor with caspase recruitment domain (ARC) protein is known to suppress both intrinsic and extrinsic apoptosis. We previously reported that ARC expression is a strong, independent adverse prognostic factor in acute myeloid leukemia (AML). Here, we investigated the regulation and role of ARC in AML. ARC expression is upregulated in AML cells co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) and suppressed by inhibition of MAPK and PI3K signaling. AML patient samples with RAS mutations (N = 64) expressed significantly higher levels of ARC than samples without RAS mutations (N = 371) (P = 0.016). ARC overexpression protected and ARC knockdown sensitized AML cells to cytarabine and to agents that selectively induce intrinsic (ABT-737) or extrinsic (TNF-related apoptosis inducing ligand) apoptosis. NOD-SCID mice harboring ARC-overexpressing KG-1 cells had significantly shorter survival than mice injected with control cells (median 84 versus 111 days) and significantly fewer leukemia cells were present when NOD/SCID IL2R null mice were injected with ARC knockdown as compared to control Molm13 cells (P = 0.005 and 0.03 at 2 and 3 weeks, respectively). Together, these findings demonstrate that MSCs regulate ARC in AML through activation of MAPK and PI3K signaling pathways. ARC confers drug resistance and survival advantage to AML in vitro and in vivo, suggesting ARC as a novel target in AML therapy. PMID:24337870

  12. Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells.

    PubMed

    Spencer, D H; Young, M A; Lamprecht, T L; Helton, N M; Fulton, R; O'Laughlin, M; Fronick, C; Magrini, V; Demeter, R T; Miller, C A; Klco, J M; Wilson, R K; Ley, T J

    2015-06-01

    HOX genes are highly expressed in many acute myeloid leukemia (AML) samples, but the patterns of expression and associated regulatory mechanisms are not clearly understood. We analyzed RNA sequencing data from 179 primary AML samples and normal hematopoietic cells to understand the range of expression patterns in normal versus leukemic cells. HOX expression in AML was restricted to specific genes in the HOXA or HOXB loci, and was highly correlated with recurrent cytogenetic abnormalities. However, the majority of samples expressed a canonical set of HOXA and HOXB genes that was nearly identical to the expression signature of normal hematopoietic stem/progenitor cells. Transcriptional profiles at the HOX loci were similar between normal cells and AML samples, and involved bidirectional transcription at the center of each gene cluster. Epigenetic analysis of a subset of AML samples also identified common regions of chromatin accessibility in AML samples and normal CD34(+) cells that displayed differences in methylation depending on HOX expression patterns. These data provide an integrated epigenetic view of the HOX gene loci in primary AML samples, and suggest that HOX expression in most AML samples represents a normal stem cell program that is controlled by epigenetic mechanisms at specific regulatory elements.

  13. Autophagy is dispensable for Kmt2a/Mll-Mllt3/Af9 AML maintenance and anti-leukemic effect of chloroquine.

    PubMed

    Chen, Xiaoyi; Clark, Jason; Wunderlich, Mark; Fan, Cuiqing; Davis, Ashley; Chen, Song; Guan, Jun-Lin; Mulloy, James C; Kumar, Ashish; Zheng, Yi

    2017-02-15

    Recently, macroautophagy/autophagy has emerged as a promising target in various types of solid tumor treatment. However, the impact of autophagy on acute myeloid leukemia (AML) maintenance and the validity of autophagy as a viable target in AML therapy remain unclear. Here we show that Kmt2a/Mll-Mllt3/Af9 AML (MA9-AML) cells have high autophagy flux compared with normal bone marrow cells, but autophagy-specific targeting, either through Rb1cc1-disruption to abolish autophagy initiation, or via Atg5-disruption to prevent phagophore (the autophagosome precursor) membrane elongation, does not affect the growth or survival of MA9-AML cells, either in vitro or in vivo. Mechanistically, neither Atg5 nor Rb1cc1 disruption impairs endolysosome formation or survival signaling pathways. The autophagy inhibitor chloroquine shows autophagy-independent anti-leukemic effects in vitro but has no efficacy in vivo likely due to limited achievable drug efficacy in blood. Further, vesicular exocytosis appears to mediate chloroquine resistance in AML cells, and exocytotic inhibition significantly enhances the anti-leukemic effect of chloroquine. Thus, chloroquine can induce leukemia cell death in vitro in an autophagy-independent manner but with inadequate efficacy in vivo, and vesicular exocytosis is a possible mechanism of chloroquine resistance in MA9-AML. This study also reveals that autophagy-specific targeting is unlikely to benefit MA9-AML therapy.

  14. High expression of costimulatory molecules correlates with low relapse-free survival probability in acute myeloid leukemia (AML).

    PubMed

    Graf, M; Reif, S; Hecht, K; Pelka-Fleischer, R; Kroell, T; Pfister, K; Schmetzer, H

    2005-05-01

    Costimulatory molecules such as lymphocyte function-associated antigen (LFA)-1 (CD11a), LFA-3 (CD58), intercellular adhesion molecule (ICAM)-1 (CD54), neuronal cell adhesion molecule (NCAM) (CD56), B7-1 (CD80), or B7-2 (CD86) are important regulatory elements in healthy immunological cascades, but their role in acute myeloid leukemia (AML) has only been rarely investigated. We studied their expression on mononuclear bone marrow (BM) cells from 105 patients with AML at initial diagnosis and evaluated their prognostic significance. Fluorescence-activated cell sorter (FACS) analyses were performed using antibodies directly conjugated with fluorescein. A BM sample was considered positive if more than 20% of the cells in the blast containing gate expressed the respective marker. The surface expression of CD11a (27 of 29 cases positive with an average of 71% positive blasts; 27(+)/29, 71%), CD54 (23(+)/33, 37%), CD56 (24(+)/93, 20%), CD58 (29(+)/29, 95%), CD80 (13(+)/28, 30%), and CD86 (19(+)/29, 39%) was measured. The expression of these markers in different French-American-British (FAB) classification types (M0-M5) was heterogeneous, except for CD56, which showed a higher proportion of positive cells in monocytic subtypes of AML. In addition, cases with a "poor risk" karyotype as well as patients succumbing to "early death" after double induction therapy according to the AML Cooperative Group (CG) protocol were characterized by a high expression of CD56. Relapse-free survival analyses demonstrated that patients with more than 8% CD56(+) cells in the BM relapsed significantly sooner. CD54 was preferentially expressed in AML M4(eo) and in addition in "favorable" cytogenetic risk groups and in cases that had responded to AML-CG therapy. Only very high proportions (>60%) of CD54(+) cells were associated with a lower probability for relapse-free survival. CD80 and CD86 expressions were similar in all FAB types. Patients who had responded to AML-CG therapy showed higher CD80

  15. Hispolon induces apoptosis through JNK1/2-mediated activation of a caspase-8, -9, and -3-dependent pathway in acute myeloid leukemia (AML) cells and inhibits AML xenograft tumor growth in vivo.

    PubMed

    Hsiao, Pei-Ching; Hsieh, Yi-Hsien; Chow, Jyh-Ming; Yang, Shun-Fa; Hsiao, Michael; Hua, Kuo-Tai; Lin, Chien-Huang; Chen, Hui-Yu; Chien, Ming-Hsien

    2013-10-23

    Hispolon is an active phenolic compound of Phellinus igniarius, a mushroom that was recently shown to have antioxidant and anticancer activities in various solid tumors. Here, the molecular mechanisms by which hispolon exerts anticancer effects in acute myeloid leukemia (AML) cells was investigated. The results showed that hispolon suppressed cell proliferation in the various AML cell lines. Furthermore, hispolon effectively induced apoptosis of HL-60 AML cells through caspases-8, -9, and -3 activations and PARP cleavage. Moreover, treatment of HL-60 cells with hispolon induced sustained activation of JNK1/2, and inhibition of JNK by JNK1/2 inhibitor or JNK1/2-specific siRNA significantly abolished the hispolon-induced activation of the caspase-8/-9/-3. In vivo, hispolon significantly reduced tumor growth in mice with HL-60 tumor xenografts. In hispolon-treated tumors, activation of caspase-3 and a decrease in Ki67-positive cells were observed. Our results indicated that hispolon may have the potential to serve as a therapeutic tool to treat AML.

  16. Survival of AML patients relapsing after allogeneic hematopoietic cell transplantation: a CIBMTR study

    PubMed Central

    Bejanyan, Nelli; Weisdorf, Daniel J.; Logan, Brent R.; Wang, Hai-Lin; Devine, Steven M.; de Lima, Marcos; Bunjes, Donald W.; Zhang, Mei-Jie

    2015-01-01

    Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a major therapeutic challenge. We studied outcomes of 1788 AML patients relapsing after alloHCT (1990–2010) during first or second complete remission (CR) to identify factors associated with longer post-relapse survival. Median time of post HCT relapse was 7 months (mo; range, 1–177). At relapse, 1231 patients (69%) received intensive therapy, including chemotherapy (CT) alone (n=660), donor lymphocyte infusion (DLI)±CT (n=202; %), or 2nd alloHCT±CT ±DLI (n=369), with subsequent CR rates of 29%. Median follow-up after relapse was 39 mo (range, <1–193). Survival for all patients was 23% at 1 year post-relapse; however, 3-yr overall survival correlated with time from HCT to relapse (4% for relapse during 1–6 mo period, 12% during 6 mo-2 yr, 26% during 2–3 yr, and 38% for ≥3 yr). In multivariable analysis, lower mortality was significantly associated with longer time from alloHCT to relapse (RR 0.55 for 6 mo-2 yr, RR 0.39 for 2–3 yr, and RR 0.28 for ≥3 yr; p<0.0001) and a 1st HCT using reduced-intensity conditioning (RR=0.77; 95% CI 0.66–0.88, p=0.0002). In contrast, inferior survival was associated with age >40 yr (RR=1.42, 95% CI 1.24–1.64; p<0.0001), active GVHD at relapse (RR=1.25, 95% CI 1.13–1.39; p<0.0001), adverse cytogenetics (RR=1.37, 95% CI 1.09–1.71; p=0.0062), mismatched URD (RR=1.61, 95% CI 1.22–2.13; p=0.0008), and use of cord blood for 1st HCT (RR=1.23, 95% CI 1.06–1.42; p=0.0078). AML relapse after alloHCT predicted poor survival; however, patients who relapsed ≥6 mo after their initial alloHCT had better survival and may benefit from intensive therapy such as 2nd alloHCT±DLI. PMID:25460355

  17. The rarity of ALDH(+) cells is the key to separation of normal versus leukemia stem cells by ALDH activity in AML patients.

    PubMed

    Hoang, Van T; Buss, Eike C; Wang, Wenwen; Hoffmann, Isabel; Raffel, Simon; Zepeda-Moreno, Abraham; Baran, Natalia; Wuchter, Patrick; Eckstein, Volker; Trumpp, Andreas; Jauch, Anna; Ho, Anthony D; Lutz, Christoph

    2015-08-01

    To understand the precise disease driving mechanisms in acute myeloid leukemia (AML), comparison of patient matched hematopoietic stem cells (HSC) and leukemia stem cells (LSC) is essential. In this analysis, we have examined the value of aldehyde dehydrogenase (ALDH) activity in combination with CD34 expression for the separation of HSC from LSC in 104 patients with de novo AML. The majority of AML patients (80 out of 104) had low percentages of cells with high ALDH activity (ALDH(+) cells; <1.9%; ALDH-rare AML), whereas 24 patients had relatively numerous ALDH(+) cells (≥1.9%; ALDH-numerous AML). In patients with ALDH-rare AML, normal HSC could be separated by their CD34(+) ALDH(+) phenotype, whereas LSC were exclusively detected among CD34(+) ALDH(-) cells. For patients with ALDH-numerous AML, the CD34(+) ALDH(+) subset consisted mainly of LSC and separation from HSC was not feasible. Functional analyses further showed that ALDH(+) cells from ALDH-numerous AML were quiescent, refractory to ARA-C treatment and capable of leukemic engraftment in a xenogenic mouse transplantation model. Clinically, resistance to chemotherapy and poor long-term outcome were also characteristic for patients with ALDH-numerous AML providing an additional risk-stratification tool. The difference in spectrum and relevance of ALDH activity in the putative LSC populations demonstrates, in addition to phenotypic and genetic, also functional heterogeneity of leukemic cells and suggests divergent roles for ALDH activity in normal HSC versus LSC. By acknowledging these differences our study provides a new and useful tool for prospective identification of AML cases in which separation of HSC from LSC is possible.

  18. Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells

    PubMed Central

    Ruvolo, Peter P.; Ruvolo, Vivian R.; Benton, Christopher B.; AlRawi, Ahmed; Burks, Jared K.; Schober, Wendy; Rolke, James; Tidmarsh, George; Hail, Numsen; Davis, R. Eric; Andreeff, Michael

    2015-01-01

    Galectin 3 (LGALS3) expression is prognostic for poor survival in acute myeloid leukemia (AML) patients. GCS-100 is a novel galectin inhibitor that may prove useful for AML therapy. In this study, we found GCS-100 induced apoptosis in AML cells. The agent reduced MCL-1 expression suggesting GCS-100 could be more effective when combined with a BH3 mimetic. Indeed, potent synergistic cytotoxicity was achieved when GCS-100 was combined with ABT-737 or ABT-199. Furthermore, the GCS-100/ABT-199 combination was effective against primary AML blast cells from patients with FLT3 ITD mutations, which is another prognostic factor for poor outcome in AML. This activity may involve wild-type p53 as shRNA knockdown of LGALS3 or galectin 1 (LGALS1) sensitized wild-type p53 OCI-AML3 cells to GCS-100/ABT-737-induced apoptosis to a much greater extent than p53 null THP-1 cells. Suppression of LGALS3 by shRNA inhibited MCL-1 expression in OCI-AML3 cells, but not THP-1 cells, suggesting the induced sensitivity to ABT-737 may involve a MCL-1 mediated mechanism. OCI-AML3 cells with LGALS1 shRNA were also sensitized to ABT-737. However, these cells exhibited increased MCL-1 expression, so MCL-1 reduction is apparently not required in this process. A role for p53 appears important as GCS-100 induces p53 expression and shRNA knockdown of p53 protected OCI-AML3 cells from the cytotoxic effects of the GCS-100/ABT-737 treatment combination. Our results suggest that galectins regulate a survival axis in AML cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199. PMID:26704388

  19. Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells.

    PubMed

    Ruvolo, Peter P; Ruvolo, Vivian R; Benton, Christopher B; AlRawi, Ahmed; Burks, Jared K; Schober, Wendy; Rolke, James; Tidmarsh, George; Hail, Numsen; Davis, R Eric; Andreeff, Michael

    2016-04-01

    Galectin 3 (LGALS3) expression is prognostic for poor survival in acute myeloid leukemia (AML) patients. GCS-100 is a novel galectin inhibitor that may prove useful for AML therapy. In this study, we found that GCS-100 induced apoptosis in AML cells. The agent reduced MCL-1 expression suggesting that GCS-100 could be more effective when combined with a BH3 mimetic. Indeed, potent synergistic cytotoxicity was achieved when GCS-100 was combined with ABT-737 or ABT-199. Furthermore, the GCS-100/ABT-199 combination was effective against primary AML blast cells from patients with FLT3 ITD mutations, which is another prognostic factor for poor outcome in AML. This activity may involve wild-type p53 as shRNA knockdown of LGALS3 or galectin 1 (LGALS1) sensitized wild-type p53 OCI-AML3 cells to GCS-100/ABT-737-induced apoptosis to a much greater extent than p53 null THP-1 cells. Suppression of LGALS3 by shRNA inhibited MCL-1 expression in OCI-AML3 cells, but not THP-1 cells, suggesting the induced sensitivity to ABT-737 may involve a MCL-1 mediated mechanism. OCI-AML3 cells with LGALS1 shRNA were also sensitized to ABT-737. However, these cells exhibited increased MCL-1 expression, so MCL-1 reduction is apparently not required in this process. A role for p53 appears important as GCS-100 induces p53 expression and shRNA knockdown of p53 protected OCI-AML3 cells from the cytotoxic effects of the GCS-100/ABT-737 treatment combination. Our results suggest that galectins regulate a survival axis in AML cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Acute myeloid leukemia (AML)-reactive cytotoxic T lymphocyte clones rapidly expanded from CD8(+) CD62L((high)+) T cells of healthy donors prevent AML engraftment in NOD/SCID IL2Rgamma(null) mice.

    PubMed

    Distler, Eva; Wölfel, Catherine; Köhler, Sylvia; Nonn, Marion; Kaus, Nina; Schnürer, Elke; Meyer, Ralf G; Wehler, Thomas C; Huber, Christoph; Wölfel, Thomas; Hartwig, Udo F; Herr, Wolfgang

    2008-04-01

    Current in vitro techniques for isolating leukemia-reactive cytotoxic T lymphocytes (CTLs) from healthy donors are of relatively low efficiency and yield responder populations with unknown biological significance. This study aimed at the development of a more reliable approach, allowing generation and expansion of acute myeloid leukemia (AML)-reactive CTLs using primary in vitro stimulation. We established allogeneic mini-mixed lymphocyte-leukemia cultures (mini-MLLCs) by stimulating donor CD8(+) T cells with human leukocyte antigen (HLA) class I-matched AML blasts in microtiter plates. Before culture, CD8(+) T cells were separated into CD62L((high)+) and CD62L((low)+/neg) subsets enriched for naive/central memory and effector memory cells, respectively. In eight different related and unrelated donor/AML pairs, numerous CTL populations were isolated that specifically lysed myeloid leukemias in association with various HLA-A, -B, or -C alleles. These CTLs expressed T-cell receptors of single Vbeta-chain families, indicating their clonal origin. The majority of CTL clones were obtained from mini-MLLCs initiated with CD62L((high)+) cells. Using antigen-specific stimulation, multiple CTL populations were amplified to 10(8)-10(10) cells within 6 to 8 weeks. Three of four representative CTL clones were capable of completely preventing engraftment of human primary AML blasts in nonobese diabetic/severe combined immune deficient IL2Rgamma(null) mice. The mini-MLLC approach allows the efficient in vitro expansion of AML-reactive CTL clones from CD8(+)CD62L((high)+) precursors of healthy donors. These CTLs can inhibit leukemia engraftment in immunodeficient mice, suggesting their potential biological relevance.

  1. The development of form two mathematics i-Think module (Mi-T2)

    NASA Astrophysics Data System (ADS)

    Yao, Foo Jing; Abdullah, Mohd Faizal Nizam Lee; Tien, Lee Tien

    2017-05-01

    This study aims to develop a training module i-THINK Mathematics Form Two (Mi-T2) to increase the higher-order thinking skills of students. The Mi-T2 training module was built based on the Sidek Module Development Model (2001). Constructivist learning theory, cognitive learning theory, i-THINK map and higher order thinking skills were the building blocks of the module development. In this study, researcher determined the validity and reliability of Mi-T2 module. The design being used in this study was descriptive study. To determine the needs of Mi-T2 module, questionnaires and literature review were used to collect data. When the need of the module was determined, the module was built and a pilot study was conducted to test the reliability of the Mi-T2 module. The pilot study was conducted at a secondary school in North Kinta, Perak. A Form Two class was selected to be the sample study through clustered random sampling. The pilot study was conducted for two months and one topic had been studied. The Mi-T2 module was evaluated by five expert panels to determine the content validity of the module. The instruments being used in the study were questionnaires about the necessity of the Mi-T2 module for guidance, questionnaires about the validity of the module and questionnaires concerning the reliability of the module. Statistical analysis was conducted to determine the validity and reliability coefficients of the Mi-T2 module. The content validity of Mi-T2 module was determined by Cohen's Kappa's (1968) agreement coefficient and the reliability of Mi-T2 module was determined by Cronbach Alpha's value scale. The content validity of Mi-T2 module was 0.89 and the Cronbach Alpha's value of Mi-T2 module was 0.911.

  2. Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients

    PubMed Central

    Fucikova, Jitka; Truxova, Iva; Hensler, Michal; Becht, Etienne; Kasikova, Lenka; Moserova, Irena; Vosahlikova, Sarka; Klouckova, Jana; Church, Sarah E.; Cremer, Isabelle; Kepp, Oliver; Kroemer, Guido; Galluzzi, Lorenzo; Salek, Cyril

    2016-01-01

    Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called “damage-associated molecular patterns,” DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from patients with acute myeloid leukemia (AML) exposed multiple DAMPs, including calreticulin (CRT), heat-shock protein 70 (HSP70), and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed CRT correlated with an increased proportion of natural killer cells and effector memory CD4+ and CD8+ T cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T cells specific for leukemia-associated antigens, indicating that ecto-CRT favors the initiation of anticancer immunity in patients with AML. Finally, although the levels of ecto-HSP70, ecto-HSP90, and ecto-CRT were all associated with improved relapse-free survival, only CRT exposure significantly correlated with superior overall survival. Thus, CRT exposure represents a novel powerful prognostic biomarker for patients with AML, reflecting the activation of a clinically relevant AML-specific immune response. PMID:27802968

  3. Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling.

    PubMed

    Hole, Paul S; Zabkiewicz, Joanna; Munje, Chinmay; Newton, Zarabeth; Pearn, Lorna; White, Paul; Marquez, Nuria; Hills, Robert K; Burnett, Alan K; Tonks, Alex; Darley, Richard L

    2013-11-07

    Excessive production of reactive oxygen species (ROS) is frequently observed in cancer and is known to strongly influence hematopoietic cell function. Here we report that extracellular ROS production is strongly elevated (mean >10-fold) in >60% of acute myeloid leukemia (AML) patients and that this increase is attributable to constitutive activation of nicotinamide adenine dinucleotide phosphate oxidases (NOX). In contrast, overproduction of mitochondrial ROS was rarely observed. Elevated ROS was found to be associated with lowered glutathione levels and depletion of antioxidant defense proteins. We also show for the first time that the levels of ROS generated were able to strongly promote the proliferation of AML cell lines, primary AML blasts, and, to a lesser extent, normal CD34(+) cells, and that the response to ROS is limited by the activation of the oxidative stress pathway mediated though p38(MAPK). Consistent with this, we observed that p38(MAPK) responses were attenuated in patients expressing high levels of ROS. These data show that overproduction of NOX-derived ROS can promote the proliferation of AML blasts and that they also develop mechanisms to suppress the stress signaling that would normally limit this response. Together these adaptations would be predicted to confer a competitive advantage to the leukemic clone.

  4. LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML.

    PubMed

    Zhou, Jianbiao; Chan, Zit-Liang; Bi, Chonglei; Lu, Xiao; Chong, Phyllis S Y; Chooi, Jing-Yuan; Cheong, Lip-Lee; Liu, Shaw-Cheng; Ching, Ying Qing; Zhou, Yafeng; Osato, Motomi; Tan, Tuan Zea; Ng, Chin Hin; Ng, Siok-Bian; Wang, Shi; Zeng, Qi; Chng, Wee-Joo

    2017-03-01

    PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thus, these results establish a novel signaling axis involving PRL-3/LIN28B/let-7, which confers stem cell-like properties to leukemia cells that is important for leukemogenesis.Implications: The current study offers a rationale for targeting PRL-3 as a therapeutic approach for a subset of AML patients with poor prognosis. Mol Cancer Res; 15(3); 294-303. ©2016 AACR.

  5. Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions.

    PubMed

    Rosenblatt, Jacalyn; Stone, Richard M; Uhl, Lynne; Neuberg, Donna; Joyce, Robin; Levine, James D; Arnason, Jon; McMasters, Malgorzata; Luptakova, Katarina; Jain, Salvia; Zwicker, Jeffrey I; Hamdan, Ayad; Boussiotis, Vassiliki; Steensma, David P; DeAngelo, Daniel J; Galinsky, Ilene; Dutt, Poorvi Somaiya; Logan, Emma; Bryant, Mary Paty; Stroopinsky, Dina; Werner, Lillian; Palmer, Kristen; Coll, Max; Washington, Abigail; Cole, Leandra; Kufe, Donald; Avigan, David

    2016-12-07

    We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells. Vaccination was also associated with a marked rise in circulating T cells recognizing whole AML cells and leukemia-specific antigens that persisted for more than 6 months. Twelve of 17 vaccinated patients (71%; 90% confidence interval, 52 to 89%) remain alive without recurrence at a median follow-up of 57 months. The results demonstrate that personalized vaccination of AML patients in remission induces the expansion of leukemia-specific T cells and may be protective against disease relapse. Copyright © 2016, American Association for the Advancement of Science.

  6. Prevalence and Prognostic Value of IDH1 R132 Mutation in Newly Diagnosed AML Egyptian Patients with Normal Karyotype.

    PubMed

    Salem, Dalia; El-Aziz, Sherin Abd; El-Menshawy, Nadia; Abouzeid, Tarek; Ebrahim, Mohamed

    2017-03-01

    Mutation in IDH1 gene was suggested to be associated with bad prognosis in cytogenetically normal AML (CN-AML). However, there are conflicting data about its prognostic impact. Besides, its prevalence and prognostic significance in Egyptian patients still not fully stated. We aimed to assess the prevalence of IDH1(R132) mutation in Egyptian CN-AML patients, its correlation with FAB subtypes, and clinical outcome of those patients. Sequencing of amplified IDH1 gene exon four from 50 patients was performed to detect codon R132 point mutation. High prevalence of IDH1 mutation was detected in our patients (9/50, 18 %). Mutated IDH1(R132) was associated with older age and higher platelets count (p = 0.04 and 0.01 respectively). The most common FAB subtype associated with mutated IDH1(R132) was AML-M2 followed by M4. In multivariate analysis, IDH1(R132) mutation was found as independent prognostic variable. It was significantly associated with lower CR and shorter OS (p = 0.06 and 0.009 respectively).

  7. High-affinity FRβ-specific CAR T cells eradicate AML and normal myeloid lineage without HSC toxicity.

    PubMed

    Lynn, R C; Feng, Y; Schutsky, K; Poussin, M; Kalota, A; Dimitrov, D S; Powell, D J

    2016-06-01

    Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here we isolated a high-affinity (HA) folate receptor beta (FRβ)-specific single-chain variable fragment (2.48 nm KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ(+) AML in vitro and in vivo compared with a low-affinity FRβ CAR (54.3 nm KD). Using the HA-FRβ immunoglobulin G, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34(+) hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T cells lysed mature CD14(+) monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T cells retained effective antitumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T cells is highly effective against AML and reduces the risk for long-term myeloid toxicity.

  8. Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients.

    PubMed

    Sakurai, M; Kunimoto, H; Watanabe, N; Fukuchi, Y; Yuasa, S; Yamazaki, S; Nishimura, T; Sadahira, K; Fukuda, K; Okano, H; Nakauchi, H; Morita, Y; Matsumura, I; Kudo, K; Ito, E; Ebihara, Y; Tsuji, K; Harada, Y; Harada, H; Okamoto, S; Nakajima, H

    2014-12-01

    Somatic mutation of RUNX1 is implicated in various hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia (AML), and previous studies using mouse models disclosed its critical roles in hematopoiesis. However, the role of RUNX1 in human hematopoiesis has never been tested in experimental settings. Familial platelet disorder (FPD)/AML is an autosomal dominant disorder caused by germline mutation of RUNX1, marked by thrombocytopenia and propensity to acute leukemia. To investigate the physiological function of RUNX1 in human hematopoiesis and pathophysiology of FPD/AML, we derived induced pluripotent stem cells (iPSCs) from three distinct FPD/AML pedigrees (FPD-iPSCs) and examined their defects in hematopoietic differentiation. By in vitro differentiation assays, FPD-iPSCs were clearly defective in the emergence of hematopoietic progenitors and differentiation of megakaryocytes, and overexpression of wild-type (WT)-RUNX1 reversed most of these phenotypes. We further demonstrated that overexpression of mutant-RUNX1 in WT-iPSCs did not recapitulate the phenotype of FPD-iPSCs, showing that the mutations were of loss-of-function type. Taken together, this study demonstrated that haploinsufficient RUNX1 allele imposed cell-intrinsic defects on hematopoietic differentiation in human experimental settings and revealed differential impacts of RUNX1 dosage on human and murine megakaryopoiesis. FPD-iPSCs will be a useful tool to investigate mutant RUNX1-mediated molecular processes in hematopoiesis and leukemogenesis.

  9. Donor-Derived Smoldering Multiple Myeloma following a Hematopoietic Cell Transplantation for AML

    PubMed Central

    Fiala, Mark; Slade, Michael; Westervelt, Peter

    2017-01-01

    Posttransplant Lymphoproliferative Disorder (PTLD) is one of the most common malignancies complicating solid organ transplantation. In contrast, PTLD accounts for a minority of secondary cancers following allogeneic hematopoietic cell transplantation (HCT). Here we report on a 61-year-old woman who received an ABO-mismatched, HLA-matched unrelated donor hematopoietic cell transplantation from a presumably healthy donor for a diagnosis of acute myeloid leukemia (AML). Eighteen months following her transplant, she developed a monoclonal gammopathy. Bone marrow studies revealed 10% plasma cells, but the patient lacked clinical defining features of multiple myeloma (MM); thus a diagnosis of smoldering multiple myeloma (SMM) was established. Cytogenetic and molecular studies of the bone marrow confirmed the plasma cells were donor-derived. The donor lacks a diagnosis of monoclonal gammopathy of undetermined significance, SMM, or MM. PMID:28316846

  10. RUNX1 and CBFβ Mutations and Activities of Their Wild-Type Alleles in AML.

    PubMed

    Hyde, R Katherine; Liu, Paul; Friedman, Alan D

    2017-01-01

    Mutations in RUNX1 and CBFB have long been recognized as important in hematological malignancies. Point mutations and deletions of RUNX1 are frequently found in myelodysplastic syndrome, myeloproliferative disease, and acute myeloid leukemia. Germline mutations in RUNX1 are associated with familial platelet disorder with predisposition to AML. In addition, as will be discussed in other chapters, both RUNX1 and CBFB are involved in recurrent chromosomal rearrangements in leukemia. More recently, roles for the non-mutated RUNX1 and CBFB genes have been identified in multiple leukemia subtypes. This chapter will discuss the roles of RUNX1 and CBFB, both in diseases caused by their mutations or deletions, as well as in the context of chromosomal rearrangements.

  11. Application of dual-fuel propulsion to a single stage AMLS vehicle

    NASA Technical Reports Server (NTRS)

    Lepsch, Roger A., Jr.; Stanley, Douglas O.; Unal, Resit

    1993-01-01

    As part of NASA's Advanced Manned Launch System (AMLS) study to determine a follow-on, or complement, to the Space Shuttle, a reusable single-stage-to-orbit concept utilizing dual-fuel rocket propulsion has been examined. Several dual-fuel propulsion concepts were investigated. These include: a separate engine concept combining Russian RD-170 kerosene-fueled engines with SSME-derivative engines; the kerosene and hydrogen-fueled Russian RD-701 engine concept; and a dual-fuel, dual-expander engine concept. Analysis to determine vehicle weight and size characteristics was performed using conceptual level design techniques. A response surface methodology for multidisciplinary design was utilized to optimize the dual-fuel vehicle concepts with respect to several important propulsion system and vehicle design parameters in order to achieve minimum empty weight. Comparisons were then made with a hydrogen-fueled reference, single-stage vehicle. The tools and methods employed in the analysis process are also summarized.

  12. G-CSF-Associated Bone Marrow Necrosis in AML after Induction Chemotherapy.

    PubMed

    Osuorji, Ikenna; Goldman, Lyle

    2012-01-01

    Bone marrow necrosis (BMN) is defined as necrosis of the myeloid tissues and stroma without involvement of the cortical bone. We report a case of 66-year-old male with AML-M4 (FAB classification) who was given induction chemotherapy with cytarabine and daunorubicin. Filgrastim at 480 micrograms was administered on days 15-19 to shorten the duration of neutropenia. Consequently patient developed severe pelvic bone pain, leukoerythroblastosis, and severe leukocytosis. Repeat bone marrow aspiration and biopsy on day 21 confirmed bone marrow necrosis. These manifestations responded quickly to discontinuation of filgrastim. Subsequently, he recovered full myelopoiesis. We suggest that there may be more cases of BMN associated with G-CSF that are undiagnosed.

  13. Donor-Derived Smoldering Multiple Myeloma following a Hematopoietic Cell Transplantation for AML.

    PubMed

    Fakhri, Bita; Fiala, Mark; Slade, Michael; Westervelt, Peter; Ghobadi, Armin

    2017-01-01

    Posttransplant Lymphoproliferative Disorder (PTLD) is one of the most common malignancies complicating solid organ transplantation. In contrast, PTLD accounts for a minority of secondary cancers following allogeneic hematopoietic cell transplantation (HCT). Here we report on a 61-year-old woman who received an ABO-mismatched, HLA-matched unrelated donor hematopoietic cell transplantation from a presumably healthy donor for a diagnosis of acute myeloid leukemia (AML). Eighteen months following her transplant, she developed a monoclonal gammopathy. Bone marrow studies revealed 10% plasma cells, but the patient lacked clinical defining features of multiple myeloma (MM); thus a diagnosis of smoldering multiple myeloma (SMM) was established. Cytogenetic and molecular studies of the bone marrow confirmed the plasma cells were donor-derived. The donor lacks a diagnosis of monoclonal gammopathy of undetermined significance, SMM, or MM.

  14. Clofarabine versus fludarabine-based reduced-intensity conditioning regimen prior to allogeneic transplantation in adults with AML/MDS.

    PubMed

    Chevallier, Patrice; Labopin, Myriam; de La Tour, Regis Peffault; Lioure, Bruno; Bulabois, Claude-Eric; Huynh, Anne; Blaise, Didier; Turlure, Pascal; Daguindau, Etienne; Maillard, Natacha; Yakoub-Agha, Ibrahim; Guillerm, Gaelle; Delage, Jeremy; Contentin, Nathalie; Bay, Jacques-Olivier; Beckerich, Florence; Bourhis, Jean-Henri; Detrait, Marie; Vigouroux, Stéphane; François, Sylvie; Legrand, Faezeh; Guillaume, Thierry; Mohty, Mohamad

    2016-11-01

    We have retrospectively compared survivals between acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received either a clofarabine/busulfan (CloB2A2) or a fludarabine/busulfan (FB2A2) RIC regimen for allogeneic stem cell transplantation. Between 2009 and 2014, 355 allotransplanted cases were identified from the SFGM-TC registry as having received either the FB2A2 (n = 316, 56% males, median age: 59.2 years, AML 78.5%, first complete remission [CR1] 72%, median follow-up: 20 months) or the CloB2A2 (n = 39, 62% males, median age: 60.8 years, AML 62%, CR1 69%, median follow-up: 22.4 months) RIC regimen. In multivariate analysis, FB2A2 was associated with significant lower overall survival (OS, HR: 2.14; 95%CI: 1.05-4.35, P = 0.04) and higher relapse incidence (RI, HR: 2.17; 95%CI: 1.02-4.61, P = 0.04) and a trend for lower leukemia-free survival (LFS, HR: 1.75; 95%CI: 0.94-3.26, P = 0.08). These results were confirmed using a propensity score-matching strategy. However, when considering AML and MDS patients separately, the benefit of the CLOB2A2 regimen was restricted to AML patients (2-year OS FB2A2: 38% [14.5-61.6] vs. CloB2A2: 79.2% [62.9-95.4], P = 0.01; 2-year LFS FB2A2: 38% [16-59.9] vs. CloB2A2: 70.8% [52.6-89], P = 0.03). The better survivals were due to the lower risk of relapse in this CloB2A2 AML subgroup (2-year RI FB2A2: 41.2% [19-62.4] vs. CloB2A2: 16.7% [5-34.2], P = 0.05). This retrospective comparison suggests that the CloB2A2 RIC regimen can likely provide longer survival than that awarded by a FB2A2 RIC regimen and may become a new standard of care RIC regimen for allotransplanted AML patients. A prospective phase 3 randomized study is warranted.

  15. Treosulfan, Fludarabine and 2 Gy Total Body Irradiation Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with MDS and AML

    PubMed Central

    Gyurkocza, Boglarka; Gutman, Jonathan; Nemecek, Eneida R.; Bar, Merav; Milano, Filippo; Ramakrishnan, Aravind; Scott, Bart; Fang, Min; Wood, Brent; Pagel, John M.; Baumgart, Joachim; Delaney, Colleen; Maziarz, Richard T.; Sandmaier, Brenda M.; Estey, Elihu H.; Appelbaum, Frederick R.; Storer, Barry E.; Deeg, H. Joachim

    2014-01-01

    Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial we assessed the efficacy and toxicity of treosulfan, fludarabine and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n=36; 15 RMCD; 10 RAEB-1; 10 RAEB-2; 1 CMML-1) or AML (n=60; 35 CR1; 18 CR2; 3 advanced CR; 4 refractory relapse) were enrolled; median age was 51 (range: 1–60) years. Twelve patients had undergone a prior HCT with high intensity conditioning. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days −6 to −4, IV fludarabine, 30 mg/m2/day on days −6 to −2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n=27) or unrelated (n=69) donors. Graft-vs.-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence and non-relapse mortality were 73%, 27% and 8%, respectively. The incidences of grades II–IV (III–IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor risk and good/intermediate risk cytogenetics (69% and 85%, respectively), or between AML patients with unfavorable and favorable/intermediate risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n=10) at the time of HCT predicted higher relapse incidence (70% vs. 18%) and lower OS (41% vs. 79%) at 2 years, when compared to patients without MRD. In conclusion, treosulfan, fludarabine and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML, and resulted in low relapse incidence, regardless

  16. WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides.

    PubMed

    Brayer, Jason; Lancet, Jeffrey E; Powers, John; List, Alan; Balducci, Lodovico; Komrokji, Rami; Pinilla-Ibarz, Javier

    2015-07-01

    Peptide vaccines are capable of eliciting immune responses targeting tumor-associated antigens such as the Wilms' Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity. Six vaccinations were delivered biweekly, continuing then monthly until patients received 12 vaccinations or showed disease relapse or progression. Therapeutic efficacy was evaluated by progression-free and overall survival. Immune responses were evaluated by delayed-type hypersensitivity testing and T-cell IFNγ ELISPOT at specified intervals. In 16 patients who received at least one vaccination, 10 completed the planned course of six vaccinations and six continued for up to six additional monthly vaccinations. Vaccinations were well tolerated, with no patients discontinuing due to toxicity. One of two patients with high-risk MDS experienced a prolonged decrease in transfusion dependence. Two of 14 AML patients demonstrated relapse-free survival >1 year. Both patients were in CR2 at time of vaccination, with duration of their remission exceeding duration of their first remission, suggesting a potential benefit. Our WT1 vaccine was well-tolerated. The clinical benefit that we observed in several patients suggests engagement of a protective immune response, indicating a need for further trials.

  17. WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides

    PubMed Central

    Brayer, Jason; Lancet, Jeffrey E.; Powers, John; List, Alan; Balducci, Lodovico; Komrokji, Rami; Pinilla-Ibarz, Javier

    2015-01-01

    Peptide vaccines are capable of eliciting immune responses targeting tumor-associated antigens such as the Wilms’ Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity. Six vaccinations were delivered biweekly, continuing then monthly until patients received 12 vaccinations or showed disease relapse or progression. Therapeutic efficacy was evaluated by progression-free and overall survival. Immune responses were evaluated by delayed-type hypersensitivity testing and T-cell IFNγ ELISPOT at specified intervals. In 16 patients who received at least one vaccination, 10 completed the planned course of six vaccinations and six continued for up to six additional monthly vaccinations. Vaccinations were well tolerated, with no patients discontinuing due to toxicity. One of two patients with high-risk MDS experienced a prolonged decrease in transfusion dependence. Two of 14 AML patients demonstrated relapse-free survival >1 year. Both patients were in CR2 at time of vaccination, with duration of their remission exceeding duration of their first remission, suggesting a potential benefit. Our WT1 vaccine was well-tolerated. The clinical benefit that we observed in several patients suggests engagement of a protective immune response, indicating a need for further trials. PMID:25802083

  18. Mixed lineage leukaemia histone methylases 1 collaborate with ERα to regulate HOXA10 expression in AML

    PubMed Central

    Yao, Jie; Fang, Li-Chao; Yang, Zai-Lin; Huang, Hui; Li, Yan; Deng, Jun; Zheng, Junsong

    2014-01-01

    HOXA10, a homeobox-containing gene involved in definitive haematopoiesis, which implicated in the pathogenesis of AML (acute myeloid leukaemia), has been studied extensively. But the regulatory mechanism that drives HOXA10 expression is still unclear. In the present paper, HOXA10 regulated by MLL1 (mixed lineage leukaemia histone methylase 1) with an epigenetic way has been demonstrated. The HOXA10 promoter contains several EREs (oestrogen response elements), including ERE1 and ERE2, which are close to the transcription start site, and are associated with E2-mediated activation of HOXA10. It has been shown that knockdown of the ERα (oestrogen receptor α) suppresses E2-mediated activation of HOXA10. Similarly, knockdown of MLL1 suppresses activation of HOXA10 and is bound to the ERE of HOXA10 promoter in an E2-dependent manner by forming complex with ERα. Knockdown of ERα affects the E2-dependent binding of MLL1 into HOXA10 EREs, suggesting critical roles of ERα in recruiting MLL on the HOXA10 promoter. More interestingly, the methylation status of histone protein H3K4 (H3 at lysine 4) with E2 is much higher than without E2 treatment in leukaemia cell. On the contrary, the methylation status of HOXA10 promoter with E2 treatment is much lower, which elevate the HOXA10 expression. Moreover, with ERα knockdown, the H3K4 methylation level is also decrease in myeloid cell. Overall, it has been clearly demonstrated that HOXA10 is transcriptionally regulated by MLL1, which, in coordination with ERα, plays a critical role in this process with epigenetic way and suggests a potential anti-E2 treatment of AML. PMID:25307539

  19. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial.

    PubMed

    Goldstone, A H; Burnett, A K; Wheatley, K; Smith, A G; Hutchinson, R M; Clark, R E

    2001-09-01

    In an attempt to improve induction chemotherapy for older patients with acute myeloid leukemia (AML),1314 patients were randomized to 1 of 3 induction treatments for 2 courses of DAT (daunorubicin, cytarabine, and thioguanine) 3 + 10, ADE (daunorubicin, cytarabine, and etoposide) 10 + 3 + 5, or MAC (mitoxantrone-cytarabine). The remission rate in the DAT arm was significantly better than ADE (62% vs 50%; P =.002) or MAC (62% vs 55%; P =.04). This benefit was seen in patients younger and older than 70 years. There were no differences between the induction schedules with respect to overall survival at 5 years (12% vs 8% vs 10%). A total of 226 patients were randomized to receive granulocyte colony-stimulating factor (G-CSF) or placebo as supportive care from day 8 after the end of treatment course 1. The remission rate or survival were not improved by G-CSF, although the median number of days to recover neutrophils to 1.0 x 10(9)/L was reduced by 5 days. Patients who entered remission (n = 371) were randomized to stop after a third course (DAT 2 + 7) or after 6 courses, ie, a subsequent COAP (cyclophosphamide, vincristine, cytarabine, and prednisolone), DAT 2 + 5, and COAP. The relapse risk (81% vs 73%), disease-free survival (16% vs 23%), and overall survival at 5 years (23% vs 22%) did not differ between the 3-course or 6-course arms. In addition to a treatment duration randomization, 362 patients were randomized to receive 12-month maintenance treatment with low-dose interferon, but no benefit was seen with respect to relapse risk, disease-free survival, or overall survival.

  20. Comments on the MIT Assessment of the Mars One Plan

    NASA Technical Reports Server (NTRS)

    Jones, Harry W.

    2015-01-01

    The MIT assessment of the Mars One mission plan reveals design assumptions that would cause significant difficulties. Growing crops in the crew chamber produces excessive oxygen levels. The assumed in-situ resource utilization (ISRU) equipment has too low a Technology Readiness Level (TRL). The required spare parts cause a large and increasing launch mass logistics burden. The assumed International Space Station (ISS) Environmental Control and Life Support (ECLS) technologies were developed for microgravity and therefore are not suitable for Mars gravity. Growing food requires more mass than sending food from Earth. The large number of spares is due to the relatively low reliability of ECLS and the low TRL of ISRU. The Mars One habitat design is similar to past concepts but does not incorporate current knowledge. The MIT architecture analysis tool for long-term settlements on the Martian surface includes an ECLS system simulation, an ISRU sizing model, and an analysis of required spares. The MIT tool showed the need for separate crop and crew chambers, the large spare parts logistics, that crops require more mass than Earth food, and that more spares are needed if reliability is lower. That ISRU has low TRL and ISS ECLS was designed for microgravity are well known. Interestingly, the results produced by the architecture analysis tool - separate crop chamber, large spares mass, large crop chamber mass, and low reliability requiring more spares - were also well known. A common approach to ECLS architecture analysis is to build a complex model that is intended to be all-inclusive and is hoped will help solve all design problems. Such models can struggle to replicate obvious and well-known results and are often unable to answer unanticipated new questions. A better approach would be to survey the literature for background knowledge and then directly analyze the important problems.

  1. The MIT TEAL Simulations and Visualizations in Electromagnetism

    NASA Astrophysics Data System (ADS)

    Belcher, John

    2007-03-01

    The Technology Enabled Active Learning (TEAL) Project at MIT has developed a broad range of 3D visualizations and simulations to foster student intuition about electromagnetic fields and phenomena (see http://web.mit.edu/8.02t/www/802TEAL3D/). In this talk we discuss the software approaches we use to create these simulations, including Macromedia Shockwave and Java 3D applets for interactive visualization, passive animations created with 3ds max, and the Dynamic Line Integral Convolution (DLIC) method for constructing time dependent representations of the electromagnetic field at close to the resolution of the computer display (Sundquist, 2003). The DLIC method, in particular, is far superior in delineating the spatial and temporal structure of fields as compared to e.g. field line displays or vector field grids. We also report on the use of these visualizations in instruction at the freshmen level. Our strong opinion is that for effective student learning, such visualizations must be embedded in a software framework for their interactive delivery. This ``guided inquiry'' framework is essential to influence and optimize what students take away from the visualizations. In our current research, we are delivering our visualizations using a commercial package, Addison Wesley's MasteringPhysics (MP), although any guided inquiry delivery system such as MP will be able to interact with our simulation software. We have released our Java 3D simulation software as open source with a liberal open source license (see http://jlearn.mit.edu/tealsim/ ), with support from the Davis Educational Foundation.

  2. Research in Boron Neutron Capture Therapy at MIT LABA

    SciTech Connect

    Yanch, J.C.; Shefer, R.E.; Klinkowstein, R.E.; Howard, W.B.; Song, H.; Blackburn, B.; Binello, E.

    1997-02-01

    A 4.1 MeV tandem electrostatic accelerator designed for research into Boron Neutron Capture Therapy (BNCT) has recently been installed in the MIT Laboratory for Accelerator Beam Applications (LABA). This accelerator uses a very high current switch mode high voltage power supply in conjunction with a multi-cusp negative ion source to supply the multimilliampere current required for clinical BNCT applications. A number of individual research projects aimed at evaluating the potential of this accelerator design as a hospital-based neutron source for radiation therapy of both tumors and rheumatoid arthritis are described here. {copyright} {ital 1997 American Institute of Physics.}

  3. Therapie des metastasierten kastrationsresistenten Prostatakarzinoms mit Abirateronacetat im klinischen Alltag.

    PubMed

    Wolff, Johannes Maria

    2017-01-01

    Abirateronacetat, das in Kombination mit Prednison/Prednisolon verabreicht wird, spielt eine wichtige Rolle in der Therapie des metastasierten kastrationsresistenten Prostatakarzinoms. Im Folgenden wurden besondere Aspekte der Therapie im klinischen Alltag zusammengestellt. Sie betreffen unter anderem die Dosierung - auch vor dem Hintergrund der Markteinführung einer neuen Formulierung von Abirateronacetat. Hinzu kommt die Verträglichkeit, vor allem in Bezug auf kardiovaskuläre und Kortikoid-bedingte Nebenwirkungen. Des Weiteren werden Kriterien genannt, nach denen die Therapie nicht zu früh umgestellt werden sollte. © 2017 S. Karger GmbH, Freiburg.

  4. Characteristics of the MIT microwiggler for free electron laser applications

    SciTech Connect

    Catravas, P.; Stoner, R.; Bekefi, G.

    1995-12-31

    We report work on the development of microwiggler technology for free electron laser research. The MIT microwiggler is a pulsed electromagnet with 70 periods of 8.8 mm each which generates a peak on-axis field of 4.2 kG. The wiggler is characterized by extensive tunability. We developed a novel tuning regimen to control 140 degrees of freedom afforded by the individually tunable half periods and achieved an rms spread in the peak amplitudes of 0.08%. This is the lowest attained to date in any sub-cm period wiggler. The microwiggler design and comprehensive measurements of its characteristics will be described.

  5. Mit Mathematik zu Mehr Intelligenz in der Logistik

    NASA Astrophysics Data System (ADS)

    Möhring, Rolf H.; Schenk, Michael

    Die Lösung logistischer Probleme ist ein wichtiger Aspekt menschlichen Handelns seit Menschen gemeinsam zielgerichtet tätig wurden. Die Grundlagen dessen, was wir heute Logistik nennen, entstammen dem militärischen Bereich. So basierte z. B. das römische Imperium in starkem Maße auf militärisch-logistischen Glanzleistungen. Ob damals bereits mathematische Überlegungen eine Rolle spielten, wissen wir heute nicht. Jedoch versuchte z. B. Napoleon, der mit den bedeutendsten Mathematikern seiner Zeit befreundet war, den Transport seiner Truppen und die Verbreitung von Informationen zu optimieren und strategisch einzusetzen.1,2

  6. The MIT-Green Bank (MG) 5 GHz survey

    NASA Technical Reports Server (NTRS)

    Bennett, C. L.; Lawrence, C. R.; Burke, B. F.; Hewitt, J. N.; Mahoney, J.

    1986-01-01

    The catalog yielded by the MIT-Green Bank 5-GHz survey contains 5974 sources with S/N ratio greater than 5; a supplemental catalog contains 3836 possible detections with S/N of less than 5. The reliability of the main list is measured to be about 96 percent, with a completeness of about 95 percent. Flux density errors are a function of flux density. A comparison is presently made of survey sources from the Douglas et al. (1980) 365-MHz Texas survey; spectral indices are computed for coincident sources, and the distribution of spectral indices is discussed.

  7. A new model to predict remission status in AML patients based on day 14 bone marrow biopsy.

    PubMed

    Norkin, Maxim; Chang, Myron; An, Qi; Leather, Helen; Katragadda, Lakshmikanth; Li, Ying; Moreb, Jan S; May, W Stratford; Brown, Randy A; Hsu, Jack W; Hiemenz, John W; Wingard, John R; Cogle, Christopher R

    2016-07-01

    Although bone marrow evaluation on day 14 after initiation of induction chemotherapy (D14 BM) is a widely accepted practice in patients with acute myeloid leukemia (AML), it has suboptimal predictive value for predicting complete remission. We retrospectively analyzed pretreatment characteristics and post-induction response in a cohort of AML patients to determine if adding clinical and laboratory characteristics can improve the predictive value of the D14 BM evaluation. Among 297 patients treated for AML at the single institution 183 patients (61%) had leukemia-positive D14 BM. Of those, 94 were given reinduction chemotherapy and 89 were not. Of the 89 patients who did not receive reinduction, 32 (36%) subsequently achieved complete remission (CR) or complete remission with incomplete count recovery (CRi), and 57 (64%) had persistent disease. Persistent disease after positive D14 BM was more likely associated with higher percentage of D14 myeloblasts, a history of relapsed disease before induction, and higher risk disease compared to patients who subsequently achieved CR. Age, diagnostic white blood cell count, and the D14 BM cellularity did not influence the subsequent likelihood of achieving remission in patients with a positive D14 BM. A new mathematical equation was created and resulted in a positive predictive value of 83%, negative predictive value 90% and accuracy 88% for correctly identifying remission status after positive D14 BM in AML. The accuracy of predicting response using these additional parameters was significantly higher than without (0.88 vs. 0.80, P=0.002). Our new model provides better accuracy for predicting the likelihood of achieving remission and if validated in future studies may be useful for managing AML patients.

  8. The Runt domain of AML1 (RUNX1) binds a sequence-conserved RNA motif that mimics a DNA element

    PubMed Central

    Fukunaga, Junichi; Nomura, Yusuke; Tanaka, Yoichiro; Amano, Ryo; Tanaka, Taku; Nakamura, Yoshikazu; Kawai, Gota; Sakamoto, Taiichi; Kozu, Tomoko

    2013-01-01

    AML1 (RUNX1) is a key transcription factor for hematopoiesis that binds to the Runt-binding double-stranded DNA element (RDE) of target genes through its N-terminal Runt domain. Aberrations in the AML1 gene are frequently found in human leukemia. To better understand AML1 and its potential utility for diagnosis and therapy, we obtained RNA aptamers that bind specifically to the AML1 Runt domain. Enzymatic probing and NMR analyses revealed that Apt1-S, which is a truncated variant of one of the aptamers, has a CACG tetraloop and two stem regions separated by an internal loop. All the isolated aptamers were found to contain the conserved sequence motif 5′-NNCCAC-3′ and 5′-GCGMGN′N′-3′ (M:A or C; N and N′ form Watson–Crick base pairs). The motif contains one AC mismatch and one base bulged out. Mutational analysis of Apt1-S showed that three guanines of the motif are important for Runt binding as are the three guanines of RDE, which are directly recognized by three arginine residues of the Runt domain. Mutational analyses of the Runt domain revealed that the amino acid residues used for Apt1-S binding were similar to those used for RDE binding. Furthermore, the aptamer competed with RDE for binding to the Runt domain in vitro. These results demonstrated that the Runt domain of the AML1 protein binds to the motif of the aptamer that mimics DNA. Our findings should provide new insights into RNA function and utility in both basic and applied sciences. PMID:23709277

  9. The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO

    PubMed Central

    Peterson, Luke F.; Yan, Ming

    2007-01-01

    The 8;21 translocation is a major contributor to acute myeloid leukemia (AML) of the M2 classification occurring in approximately 40% of these cases. Multiple mouse models using this fusion protein demonstrate that AML1-ETO requires secondary mutagenic events to promote leukemogenesis. Here, we show that the negative cell cycle regulator p21WAF1 gene is up-regulated by AML1-ETO at the protein, RNA, and promoter levels. Retroviral transduction and hematopoietic cell transplantation experiments with p21WAF1-deficient cells show that AML1-ETO is able to promote leukemogenesis in the absence of p21WAF1. Thus, loss of p21WAF1 facilitates AML1-ETO–induced leukemogenesis, suggesting that mutagenic events in the p21WAF1 pathway to bypass the growth inhibitory effect from AML1-ETO–induced p21WAF1 expression can be a significant factor in AML1-ETO–associated acute myeloid leukemia. PMID:17284535

  10. Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2

    PubMed Central

    Karathedath, Sreeja; Rajamani, Bharathi M.; Musheer Aalam, Syed Mohammed; Abraham, Ajay; Varatharajan, Savitha; Krishnamurthy, Partha; Mathews, Vikram; Velayudhan, Shaji Ramachandran

    2017-01-01

    Cytarabine (Ara-C) and Daunorubicin (Dnr) forms the backbone of acute myeloid leukemia (AML) therapy. Drug resistance and toxic side effects pose a major threat to treatment success and hence alternate less toxic therapies are warranted. NF-E2 related factor-2 (Nrf2), a master regulator of antioxidant response is implicated in chemoresistance in solid tumors. However, little is known about the role of Nrf2 in AML chemoresistance and the effect of pharmacological inhibitor brusatol in modulating this resistance. Primary AML samples with high ex-vivo IC50 to Ara-C, ATO, Dnr had significantly high NRF2 RNA expression. Gene-specific knockdown of NRF2 improved sensitivity to these drugs in resistant AML cell lines by decreasing the expression of downstream antioxidant targets of Nrf2 by compromising the cell’s ability to scavenge the ROS. Treatment with brusatol, a pharmacological inhibitor of Nrf2, improved sensitivity to Ara-C, ATO, and Dnr and reduced colony formation capacity. AML cell lines stably overexpressing NRF2 showed increased resistance to ATO, Dnr and Ara-C and increased expression of downstream targets. This study demonstrates that Nrf2 could be an ideal druggable target in AML, more so to the drugs that function through ROS, suggesting the possibility of using Nrf2 inhibitors in combination with chemotherapeutic agents to modulate drug resistance in AML. PMID:28505160

  11. Arsenic trioxide and all-trans-retinoic acid selectively exert synergistic cytotoxicity against FLT3-ITD AML cells via co-inhibition of FLT3 signaling pathways.

    PubMed

    Wang, Li-Na; Tang, Yan-Lai; Zhang, Yin-Chuan; Zhang, Zu-Han; Liu, Xiao-Jian; Ke, Zhi-Yong; Li, Yu; Tan, Hui-Zhen; Huang, Li-Bin; Luo, Xue-Qun

    2017-03-09

    FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors have in vitro but limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML. Here, we demonstrate that an ATO/ATRA combination selectively exerts synergistic cytotoxicity against FLT3-ITD AML cell lines (MV4;11/MOLM-13). The signaling pathways affected by ATO/ATRA include FLT3/STAT5/MYC, FLT3/STAT5/E2F1, FLT3/ERK/ATF5 and FLT3/AKT/ATF5.ATF5 may function as an oncogene in FLT3-ITD AML. Our findings provide experimental evidence that supports further exploration of ATO/ATRA in FLT3-ITD AML in vivo and warrants a clinical evaluation of regimens comprising an ATO/ATRA combination.

  12. Helicobacter sp. MIT 01-6451 infection during fetal and neonatal life in laboratory mice.

    PubMed

    Yamanaka, Hitoki; Nakanishi, Tai; Takagi, Toshikazu; Ohsawa, Makiko; Kubo, Noriaki; Yamamoto, Naoto; Takemoto, Takahira; Ohsawa, Kazutaka

    2015-01-01

    Helicobacter sp. MIT 01-6451 has been detected in SPF mice kept in Japan. To characterize strain MIT 01-6451, its infection route during fetal and neonatal life and effects on pregnancy were investigated using immunocompetent and immunodeficient mouse strains (BALB/c, C57BL/6, and SCID). MIT 01-6451 was detected in the uterus, vagina, and mammary glands of 50% of infected SCID mice, whereas these tissues were all negative in immunocompetent mice. No fetal infections with MIT 01-6451 were detected at 16-18 days after pregnancy in any mouse strain. In newborn mice, MIT 01-6451 was detected in intestinal tissue of C57BL/6 and SCID mice at 9-11 days after birth, but not in BALB/c mice. The IgA and IgG titers to MIT 01-6451 in sera of C57BL/6 female mice were significantly lower than those of BALB/c mice. Although no significant differences in the number of newborns per litter were observed between MIT 01-6451-infected and MIT 01-6451-free dams, the birth rate was lower in infected SCID mice than in control SCID mice. The present results indicated that MIT 01-6451 infects newborn mice after birth rather than by vertical transmission to the fetus via the placenta and that MIT 01-6451 infection shows opportunistically negative effects on the birth rate. In addition, the maternal immune response may affect infection of newborn mice with MIT 01-6451 through breast milk.

  13. Helicobacter sp. MIT 01-6451 infection during fetal and neonatal life in laboratory mice

    PubMed Central

    Yamanaka, Hitoki; Nakanishi, Tai; Takagi, Toshikazu; Ohsawa, Makiko; Kubo, Noriaki; Yamamoto, Naoto; Takemoto, Takahira; Ohsawa, Kazutaka

    2015-01-01

    Helicobacter sp. MIT 01-6451 has been detected in SPF mice kept in Japan. To characterize strain MIT 01-6451, its infection route during fetal and neonatal life and effects on pregnancy were investigated using immunocompetent and immunodeficient mouse strains (BALB/c, C57BL/6, and SCID). MIT 01-6451 was detected in the uterus, vagina, and mammary glands of 50% of infected SCID mice, whereas these tissues were all negative in immunocompetent mice. No fetal infections with MIT 01-6451 were detected at 16–18 days after pregnancy in any mouse strain. In newborn mice, MIT 01-6451 was detected in intestinal tissue of C57BL/6 and SCID mice at 9–11 days after birth, but not in BALB/c mice. The IgA and IgG titers to MIT 01-6451 in sera of C57BL/6 female mice were significantly lower than those of BALB/c mice. Although no significant differences in the number of newborns per litter were observed between MIT 01-6451-infected and MIT 01-6451-free dams, the birth rate was lower in infected SCID mice than in control SCID mice. The present results indicated that MIT 01-6451 infects newborn mice after birth rather than by vertical transmission to the fetus via the placenta and that MIT 01-6451 infection shows opportunistically negative effects on the birth rate. In addition, the maternal immune response may affect infection of newborn mice with MIT 01-6451 through breast milk. PMID:26134357

  14. Educational Outreach at the MIT Plasma Science and Fusion Center

    NASA Astrophysics Data System (ADS)

    Rivenberg, Paul; Thomas, Paul

    2004-11-01

    At the MIT PSFC student and staff volunteers work together to increase the public's knowledge of fusion science and plasma technology. Seeking to generate excitement in young people about science and engineering, the PSFC hosts a number of educational outreach activities and tours throughout the year, including Middle and High School Outreach Days. The PSFC also has an in-school science demonstration program on the theme of magnetism. As ''Mr. Magnet'' Technical Supervisor Paul Thomas brings a truck-load of hands-on demonstrations to K-12 schools, challenging students to help him with experiments. While teaching fundamentals of magnetism and electricity he shows that science is fun for all, and that any student can have a career in science. This year he taught at 75 schools and other events, reaching 30,000 teachers and students. He has expanded his teaching to include an interactive demonstration of plasma, encouraging participants to investigate plasma properties with audiovisual, electromagnetic, and spectroscopic techniques. The PSFC's continuing involvement with the MIT Museum and the Boston Museum of Science also helps familiarize the public with the fourth state of matter.

  15. Quark orbital angular momentum in the MIT bag model

    NASA Astrophysics Data System (ADS)

    Courtoy, A.; Miramontes, A. S.

    2017-01-01

    We present the results for the generalized transverse momentum distribution related to quark orbital angular momentum, i.e., F14, in the MIT bag model. This model has been modified to include the Peierls-Yoccoz projection to restore translational invariance. Such a modification allows us to fulfil more satisfactorily basic sum rules that would otherwise be less elegantly carried out with the original version. Using the same model, we have calculated the twist-3 generalized parton distribution (GPD) that corresponds to orbital angular momentum à la Ji, through the Penttinen-Polyakov-Shuvaev-Strikman sum rule. Recently, a new relation between the two definitions of the quark orbital angular momentum at the density level has been proposed, which we illustrate here within the model. The sum rule is fulfilled. Still within the framework of the MIT bag model, we analyze the Wandzura-Wilczek expression for the GPD of interest. The genuine quark-gluon contribution is evaluated directly thanks to the equation of motion of the bag, which allows for a direct control of the kinematical contributions to the twist-3 GPD.

  16. Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner.

    PubMed

    Nabissi, Massimo; Morelli, Maria Beatrice; Amantini, Consuelo; Liberati, Sonia; Santoni, Matteo; Ricci-Vitiani, Lucia; Pallini, Roberto; Santoni, Giorgio

    2015-10-15

    Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor initiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml-1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml-1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml-1 spliced variants (Aml-1a, b and c) in GSCs and during their differentiation. We found that Aml-1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differentiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differentiation, we evaluated if Aml-1a interacted directly with TRPV2 promoters. Herein, we found that Aml-1a binds TRPV2 promoters and that Aml-1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Altogether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs.

  17. Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML

    PubMed Central

    Mahmud, Hasan; Scherpen, Frank J.G.; de Boer, Tiny Meeuwsen; Lourens, Harm-Jan; Schoenherr, Caroline; Eder, Matthias; Scherr, Michaela; Guryev, Victor; De Bont, Eveline S.

    2017-01-01

    The t(8;21) (q22;q22) chromosomal translocation is one of the most frequent genetic alterations in acute myeloid leukemia (AML) which has a need for improved therapeutic strategies. We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to NBM or CN-AML in our previous peptide microarray. PLC-γ1 is known to play a role in cancer progression, however, the impact of PLC-γ1 in AML is currently unknown. Therefore, we aimed to study the functional role of PLC-γ1 by investigating the cellular growth, survival and its underlying mechanism in t(8;21) AML. In this study, PLC-γ1 expression was significantly higher in t(8;21) AML compared to other karyotypes. The PLC-γ1 protein expression was suppressed in AML1-ETO knock down cells indicating that it might induce kasumi-1 cell death. ShRNA-mediated PLC-γ1 knockdown in kasumi-1 cells significantly blocked cell growth, induced apoptosis and cell cycle arrest which was explained by the increased activation of apoptotic related and cell cycle regulatory protein expressions. Gene expression array analysis showed the up-regulation of apoptotic and DNA damage response genes together with the downregulation of cell growth, proliferation and differentiation genes in the PLC-γ1 suppressed kasumi-1 cells, consistent with the observed phenotypic effects. Importantly, PLC-γ1 suppressed kasumi-1 cells showed higher chemosensitivity to the chemotherapeutic drug treatments and lower cell proliferation upon hypoxic stress. Taken together, these in vitro finding strongly support an important role for PLC-γ1 in the survival of t(8;21) AML mimicking kasumi-1 cells and identify PLC-γ1 as a potential therapeutic target for t(8;21) AML treatment.

  18. Feasibility of the AML profiler (Skyline™ Array) for patient risk stratification in a multicentre trial: a preliminary comparison with the conventional approach.

    PubMed

    Nomdedéu, Josep F; Puigdecanet, Eulalia; Bussaglia, Elena; Hernández, Juan José; Carricondo, Maite; Estivill, Camino; Martí-Tutusaus, Josep Maria; Tormo, Mar; Zamora, Lurdes; Serrano, Elena; Perea, Granada; de Llano, Maria Paz Queipo; García, Antoni; Sánchez-Ortega, Isabel; Ribera, Josep Maria; Nonell, Lara; Aventin, Anna; Solé, Francesc; Brunet, Maria Salut; Sierra, Jorge

    2016-05-03

    Deoxyribonucleic acid microarrays allow researchers to measure mRNA levels of thousands of genes in a single experiment and could be useful for diagnostic purposes in patients with acute myeloid leukaemia (AML). We assessed the feasibility of the AML profiler (Skyline™ Array) in genetic stratification of patients with de novo AML and compared the results with those obtained using the standard cytogenetic and molecular approach. Diagnostic bone marrow from 31 consecutive de novo AML cases was used to test MLL-PTD, FLT3-ITD and TKD, NPM1 and CEBPAdm mutations. Purified RNA was used to assess RUNX1-RUNX1T1, PML-RARα and CBFβ-MYH11 rearrangements. RNA remnants underwent gene expression profiling analysis using the AML profiler, which detects chromosomal aberrations: t(8;21), t(15;17), inv(16), mutations (CEBPAdm, ABD-NPM1) and BAALC and EVI1 expression. Thirty cases were successfully analysed with both methods. Five cases had FLT3-ITD. In one case, a t(8;21) was correctly detected by both methods. Four cases had inv(16); in one, the RNA quality was unsatisfactory and it was not hybridized, and in the other three, the AML profiler detected the genetic lesion - this being a rare type I translocation in one case. Two cases with acute promyelocytic leukaemia were diagnosed by both methods. Results for NPM1 mutations were concordant in all but two cases (2/11, non-ABD mutations). Analysis of costs and turnaround times showed that the AML profiler was no more expensive than the conventional molecular approach. These results suggest that the AML profiler could be useful in multicentre trials to rapidly identify patients with AML with a good prognosis. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Polymorphisms and haplotypes of the CYP2B6 detoxification gene in the predisposition of Acute Myeloid Leukemia (AML) and induction of its cytogenetic abnormalities.

    PubMed

    Daraki, Aggeliki; Kakosaiou, Katerina; Zachaki, Sophia; Sambani, Constantina; Aleporou-Marinou, Vassiliki; Kollia, Panagoula; Manola, Kalliopi N

    2016-11-01

    CYP2B6 is a polymorphic detoxification gene which plays a vital role in the degradation of genotoxic compounds. In this study we hypothesized that inadequate detoxification due to CYP2B6 polymorphisms may contribute to AML. To evaluate the potential impact of CYP2B6 polymorphisms on AML development and induction of its specific chromosomal abnormalities we studied C(777)A and A(785)G polymorphisms for the first time in AML. Furthermore, we investigated the co-existence of the above polymorphisms with G(516)T polymorphism to determine the CYP2B6 high-risk haplotypes in AML susceptibility. Our study included 619 AML patients and 430 healthy donors. Concerning C(777)A CYP2B6 polymorphism, no significant difference was found between patients and controls. However, A(785)G CYP2B6 polymorphism showed a statistically higher frequency of the variant genotypes in patients (48.2%), mainly in secondary AML patients (49.1%) than in controls (26.1%). Moreover, an increased frequency of the variant genotypes was found in those with abnormal karyotypes, especially with -7/del(7q), -5/del(5q), +8, inv(16) and t(8;21). The combination of the three CYP2B6 polymorphisms (G(516)T, C(777)A & A(785)G) revealed seven haplotypes. Four out of six haplotypes with at least one mutant allele were significantly associated with an increased risk for AML. Interestingly, T516A777G785 haplotype, where the three mutant alleles co-existed, had ~3-fold increased risk to be found in patients than controls. The association between haplotypes and cytogenetic aberrations revealed a positive correlation between specific CYP2B6 haplotypes and AML cytogenetic abnormalities. Our data suggest that A(785)G CYP2B6 gene polymorphism and specific CYP2B6 haplotypes may contribute to AML and its specific chromosomal aberrations.

  20. Genomic DNA breakpoints in AML1/RUNX1 and ETO cluster with topoisomerase II DNA cleavage and DNase I hypersensitive sites in t(8;21) leukemia

    PubMed Central

    Zhang, Yanming; Strissel, Pamela; Strick, Reiner; Chen, Jianjun; Nucifora, Giuseppina; Le Beau, Michelle M.; Larson, Richard A.; Rowley, Janet D.

    2002-01-01

    The translocation t(8;21)(q22;q22) is one of the most frequent chromosome translocations in acute myeloid leukemia (AML). AML1/RUNX1 at 21q22 is involved in t(8;21), t(3;21), and t(16;21) in de novo and therapy-related AML and myelodysplastic syndrome as well as in t(12;21) in childhood B cell acute lymphoblastic leukemia. Although DNA breakpoints in AML1 and ETO (at 8q22) cluster in a few introns, the mechanisms of DNA recombination resulting in t(8;21) are unknown. The correlation of specific chromatin structural elements, i.e., topoisomerase II (topo II) DNA cleavage sites, DNase I hypersensitive sites, and scaffold-associated regions, which have been implicated in chromosome recombination with genomic DNA breakpoints in AML1 and ETO in t(8;21) is unknown. The breakpoints in AML1 and ETO were clustered in the Kasumi 1 cell line and in 31 leukemia patients with t(8;21); all except one had de novo AML. Sequencing of the breakpoint junctions revealed no common DNA motif; however, deletions, duplications, microhomologies, and nontemplate DNA were found. Ten in vivo topo II DNA cleavage sites were mapped in AML1, including three in intron 5 and seven in intron 7a, and two were in intron 1b of ETO. All strong topo II sites colocalized with DNase I hypersensitive sites and thus represent open chromatin regions. These sites correlated with genomic DNA breakpoints in both AML1 and ETO, thus implicating them in the de novo 8;21 translocation. PMID:11867721

  1. M.I.T. and the Federal Government. An Examination of the Effects of Government Regulation and Research Support on Selected Parts of M.I.T.

    ERIC Educational Resources Information Center

    Garvin, David

    A self-study was undertaken at the Massachusetts Institute of Technology (M.I.T.) to examine the impact of the federal government on it. M.I.T. is a large institution with an enrollment of 8,000, a faculty of 950, and a total teaching staff of 1,700. Of its operating expenses by far the largest source of funds in recent years has been sponsored…

  2. Mobile-IT Education (MIT.EDU): M-Learning Applications for Classroom Settings

    ERIC Educational Resources Information Center

    Sung, M.; Gips, J.; Eagle, N.; Madan, A.; Caneel, R.; DeVaul, R.; Bonsen, J.; Pentland, A.

    2005-01-01

    In this paper, we describe the Mobile-IT Education (MIT.EDU) system, which demonstrates the potential of using a distributed mobile device architecture for rapid prototyping of wireless mobile multi-user applications for use in classroom settings. MIT.EDU is a stable, accessible system that combines inexpensive, commodity hardware, a flexible…

  3. MIT domain of Vps4 is a Ca2+-dependent phosphoinositide-binding domain.

    PubMed

    Iwaya, Naoko; Takasu, Hirotoshi; Goda, Natsuko; Shirakawa, Masahiro; Tanaka, Toshiki; Hamada, Daizo; Hiroaki, Hidekazu

    2013-05-01

    The microtubule interacting and trafficking (MIT) domain is a small protein module that is conserved in proteins of diverged function, such as Vps4, spastin and sorting nexin 15 (SNX15). The molecular function of the MIT domain is protein-protein interaction, in which the domain recognizes peptides containing MIT-interacting motifs. Recently, we identified an evolutionarily related domain, 'variant' MIT domain at the N-terminal region of the microtubule severing enzyme katanin p60. We found that the domain was responsible for binding to microtubules and Ca(2+). Here, we have examined whether the authentic MIT domains also bind Ca(2+). We found that the loop between the first and second α-helices of the MIT domain binds a Ca(2+) ion. Furthermore, the MIT domains derived from Vps4b and SNX15a showed phosphoinositide-binding activities in a Ca(2+)-dependent manner. We propose that the MIT domain is a novel membrane-associating domain involved in endosomal trafficking.

  4. Scratch that: MIT's Mitchel Resnick Says Kids Should Do It for Themselves

    ERIC Educational Resources Information Center

    Traylor, Scott

    2008-01-01

    Mitchel Resnick is a researcher, inventor, and professor at MIT's Media Laboratory in Cambridge, MA, and the founder of the Lifelong Kindergarten Group at MIT. He is the lead innovator behind many cutting-edge learning technologies and projects for children, including the Computer Clubhouse, PicoCrickets, and the wildly successful consumer…

  5. MIT(1), a black mamba toxin with a new and highly potent activity on intestinal contraction.

    PubMed

    Schweitz, H; Pacaud, P; Diochot, S; Moinier, D; Lazdunski, M

    1999-11-19

    Mamba intestinal toxin (MIT(1)) isolated from Dendroaspis polylepis venom is a 81 amino acid polypeptide cross-linked by five disulphide bridges. MIT(1) has a very potent action on guinea-pig intestinal contractility. MIT(1) (1 nM) potently contracts longitudinal ileal muscle and distal colon, and this contraction is equivalent to that of 40 mM K(+). Conversely MIT(1) relaxes proximal colon again as potently as 40 mM K(+). The MIT(1)-induced effects are antagonised by tetrodotoxin (1 microM) in proximal and distal colon but not in longitudinal ileum. The MIT(1)-induced relaxation of the proximal colon is reversibly inhibited by the NO synthase inhibitor L-NAME (200 microM). (125)I-labelled MIT(1) binds with a very high affinity to both ileum and brain membranes (K(d)=1.3 pM and 0.9 pM, and B(max)=30 fmol/mg and 26 fmol/mg, respectively). MIT(1) is a very highly selective toxin for a receptor present both in the CNS and in the smooth muscle and which might be an as yet unidentified K(+) channel.

  6. Scratch that: MIT's Mitchel Resnick Says Kids Should Do It for Themselves

    ERIC Educational Resources Information Center

    Traylor, Scott

    2008-01-01

    Mitchel Resnick is a researcher, inventor, and professor at MIT's Media Laboratory in Cambridge, MA, and the founder of the Lifelong Kindergarten Group at MIT. He is the lead innovator behind many cutting-edge learning technologies and projects for children, including the Computer Clubhouse, PicoCrickets, and the wildly successful consumer…

  7. Mobile-IT Education (MIT.EDU): M-Learning Applications for Classroom Settings

    ERIC Educational Resources Information Center

    Sung, M.; Gips, J.; Eagle, N.; Madan, A.; Caneel, R.; DeVaul, R.; Bonsen, J.; Pentland, A.

    2005-01-01

    In this paper, we describe the Mobile-IT Education (MIT.EDU) system, which demonstrates the potential of using a distributed mobile device architecture for rapid prototyping of wireless mobile multi-user applications for use in classroom settings. MIT.EDU is a stable, accessible system that combines inexpensive, commodity hardware, a flexible…

  8. Assessing International Product Design and Development Graduate Courses: The MIT-Portugal Program

    ERIC Educational Resources Information Center

    Dori, Yehudit Judy; Silva, Arlindo

    2010-01-01

    The Product Design and Development (PDD) course is part of the graduate curriculum in the Engineering Design and Advanced Manufacturing (EDAM) study in the MIT-Portugal Program. The research participants included about 110 students from MIT, EDAM, and two universities in Portugal, Instituto Superior Técnico-Universidade Técnica de Lisboa (IST) and…

  9. Saponin-Based Nanoemulsification Improves the Antioxidant Properties of Vitamin A and E in AML-12 Cells

    PubMed Central

    Choudhry, Qaisra Naheed; Kim, Mi Jeong; Kim, Tae Gyun; Pan, Jeong Hoon; Kim, Jun Ho; Park, Sung Jin; Lee, Jin Hyup; Kim, Young Jun

    2016-01-01

    Our work aimed to investigate the protective effects of saponin-based nanoemulsions of vitamin A and E against oxidative stress-induced cellular damage in AML-12 cells. Saponin nanoemulsions of vitamin A (SAN) and vitamin E (SEN) were prepared by high-pressure homogenization and characterized in terms of size, zeta potential, and polydispersity index. SEN and SAN protect AML-12 cells against oxidative stress-induced cellular damage more efficiently via scavenging reactive oxygen species (ROS), and reducing DNA damage, protein carbonylation, and lipid peroxidation. These results provide valuable information for the development of nanoemulsion-based delivery systems that would improve the antioxidant properties of vitamin A and E. PMID:27571071

  10. Early mixed T-cell chimerism is predictive of pediatric AML or MDS relapse after hematopoietic stem cell transplant.

    PubMed

    Broglie, Larisa; Helenowski, Irene; Jennings, Lawrence J; Schafernak, Kristian; Duerst, Reggie; Schneiderman, Jennifer; Tse, William; Kletzel, Morris; Chaudhury, Sonali

    2017-03-07

    Patients with acute myeloid leukemia (AML) who relapse after hematopoietic stem cell transplantation (HCT) have dismal outcomes. Our ability to predict those at risk for relapse is limited. We examined chimerism trends post-HCT in 63 children who underwent HCT for AML or myelodysplastic syndrome (MDS). Mixed T-cell chimerism at engraftment and absence of chronic graft versus host disease (cGVHD) were associated with relapse (P = 0.04 and P = 0.02, respectively). Mixed T-cell chimerism at engraftment was predictive in patients without cGVHD (P = 0.03). Patients with engraftment mixed T-cell chimerism may warrant closer disease monitoring and consideration for early intervention.

  11. Autophagy mediates proteolysis of NPM1 and HEXIM1 and sensitivity to BET inhibition in AML cells

    PubMed Central

    Huang, Min; Garcia, Jacqueline S.; Thomas, Daniel; Zhu, Li; Nguyen, Le Xuan Truong; Chan, Steven M.; Majeti, Ravindra; Medeiros, Bruno C.; Mitchell, Beverly S.

    2016-01-01

    The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells. PMID:27732946

  12. [R]MIT Research Centre at Delft University of Technology: A Bridge between Research, Education, Society and Profession

    ERIC Educational Resources Information Center

    Zijlstra, Hielkje

    2009-01-01

    In 2006, we launched the [R]MIT Research Centre (Modification, Intervention Transformation) at the Faculty of Architecture at Delft University of Technology. [R]MIT was founded to respond to the need for an integrated, multi-disciplinary approach to the transformation of the built environment. [R]MIT aims to bring momentum to the renewal of…

  13. Celastrol Induces Cell Apoptosis and Inhibits the Expression of the AML1-ETO/C-KIT Oncoprotein in t(8;21) Leukemia.

    PubMed

    Yu, Xianjun; Ruan, Xuzhi; Zhang, Jingxuan; Zhao, Qun

    2016-04-30

    Resistance to chemotherapy is a major challenge to improving overall survival in Acute Myeloid Leukemia (AML). Therefore, the development of innovative therapies and the identification of more novel agents for AML are urgently needed. Celastrol, a compound extracted from the Chinese herb Tripterygium wilfordii Hook, exerts anticancer activity. We investigated the effect of celastrol in the t(8;21) AML cell lines Kasumi-1 and SKNO-1. We demonstrated that inhibition of cell proliferation activated caspases and disrupted mitochondrial function. In addition, we found that celastrol downregulated the AML1-ETO fusion protein, therefore downregulating C-KIT kinases and inhibiting AKT, STAT3 and Erk1/2. These findings provide clear evidence that celastrol might provide clinical benefits to patients with t(8;21) leukemia.

  14. A Jehovah's Witness with Acute Myeloid Leukemia Successfully Treated with an Epigenetic Drug, Azacitidine: A Clue for Development of Anti-AML Therapy Requiring Minimum Blood Transfusions

    PubMed Central

    Yamamoto, Yumi; Kawashima, Akihito; Kashiwagi, Eri

    2014-01-01

    Therapy for acute leukemia in Jehovah's Witnesses patients is very challenging because of their refusal to accept blood transfusions, a fundamental supportive therapy for this disease. These patients are often denied treatment for fear of treatment-related death. We present the first Jehovah's Witness patient with acute myeloid leukemia (AML) treated successfully with azacitidine. After achieving complete remission (CR) with one course of azacitidine therapy, the patient received conventional postremission chemotherapy and remained in CR. In the case of patients who accept blood transfusions, there are reports indicating the treatment of AML patients with azacitidine. In these reports, azacitidine therapy was less toxic, including hematoxicity, compared with conventional chemotherapy. The CR rate in azacitidine-treated patients was inadequate; however, some characteristics could be useful in predicting azacitidine responders. The present case is useful for treating Jehovah's Witnesses patients with AML and provides a clue for anti-AML therapy requiring minimum blood transfusions. PMID:25371835

  15. Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity

    PubMed Central

    Liu, Yizhou; Chen, Wei; Gaudet, Justin; Cheney, Matthew D.; Roudaia, Liya; Cierpicki, Tomasz; Klet, Rachel C.; Hartman, Kari; Laue, Thomas M.; Speck, Nancy A.; Bushweller, John H.

    2007-01-01

    Summary AML1/ETO results from the t(8;21) associated with 12-15% of acute myeloid leukemia. The AML1/ETO MYND domain mediates interactions with the co-repressors SMRT and N-CoR and contributes to AML1/ETO's ability to repress proliferation and differentiation of primary bone marrow cells as well as to enhance their self-renewal in vitro. We solved the solution structure of the MYND domain and show it to be structurally homologous to the PHD and RING finger families of proteins. We also determined the solution structure of an MYND-SMRT peptide complex. We demonstrated that a single amino acid substitution that disrupts the interaction between the MYND domain and the SMRT peptide attenuated AML1/ETO's effects on proliferation, differentiation, and gene expression. PMID:17560331

  16. Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice

    PubMed Central

    Etchin, J; Montero, J; Berezovskaya, A; Le, BT; Kentsis, A; Christie, AL; Conway, AS; Chen, WC; Reed, C; Mansour, MR; Ng, CEL; Adamia, S; Rodig, SJ; Galinsky, IA; Stone, RM; Klebanov, B; Landesman, Y; Kauffman, M; Shacham, S; Kung, AL; Wang, JCY; Letai, A; Look, AT

    2016-01-01

    Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone. PMID:26202935

  17. Coupling parameters of the MIT OBS at two nearshore sites

    NASA Astrophysics Data System (ADS)

    Tréhu, Anne M.; Solomon, Sean C.

    1981-03-01

    A model representing the coupling of an ocean-bottom seismometer (OBS) to the seafloor as a mass-spring-dashpot system satisfactorily explains the results of transient tests performed on different instruments during the Lopez Island intercomparison test. In this paper, we compare the results obtained for the MIT OBS at Lopez Island to results from similar tests at a dockside site at Woods Hole, Massachusetts. The vertical instrument response at the Lopez Island site shows a highly damped resonance at a frequency of 22 Hz, whereas the response at the Woods Hole site shows a marked resonance at 13 Hz. The difference between the responses at the two sites can be qualitatively attributed to the difference between the surficial sediments.

  18. The third MIT-Green Bank 5 GHz survey

    SciTech Connect

    Griffith, M.; Heflin, M.; Conner, S.; Lehar, J.; Langston, G. National Radio Astronomy Observatory, Charlottesville, VA )

    1990-09-01

    The third MIT-Green Bank survey, which covers 1.11 sr in the right ascension range from 16.5 h to 5 h between +17 deg and +39.15 deg declination, is presented. The survey is unique in that a sample was observed twice in a short period of time and the spectral indices between 5 and 1.4 GHz are available for most of the sources brighter than 90 mJy. This survey can be used as the starting point for a search for gravitational lenses. The source list can also be examined for clustering and used to estimate the surface density of sources as a function of limiting flux density. 10 refs.

  19. Graft Immune Cell Composition Associates with Clinical Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with AML.

    PubMed

    Impola, Ulla; Larjo, Antti; Salmenniemi, Urpu; Putkonen, Mervi; Itälä-Remes, Maija; Partanen, Jukka

    2016-01-01

    Complications of allogeneic hematopoietic stem cell transplantation (HSCT) have been attributed to immune cells transferred into the patient with the graft. However, a detailed immune cell composition of the graft is usually not evaluated. In the present study, we determined the level of variation in the composition of immune cells between clinical HSCT grafts and whether this variation is associated with clinical outcome. Sizes of major immune cell populations in 50 clinical grafts from a single HSCT Centre were analyzed using flow cytometry. A statistical comparison between cell levels and clinical outcomes of HSCT was performed. Overall survival, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), and relapse were used as the primary endpoints. Individual HSCT grafts showed considerable variation in their numbers of immune cell populations, including CD123(+) dendritic cells and CD34(+) cells, which may play a role in GVHD. Acute myeloid leukemia (AML) patients who developed aGVHD were transplanted with higher levels of effector CD3(+) T, CD19(+) B, and CD123(+) dendritic cells than AML patients without aGVHD, whereas grafts with a high CD34(+) content protected against aGVHD. AML patients with cGVHD had received grafts with a lower level of monocytes and a higher level of CD34(+) cells than those without cGVHD. There is considerable variation in the levels of immune cell populations between HSCT grafts, and this variation is associated with outcomes of HSCT in AML patients. A detailed analysis of the immune cell content of the graft can be used in risk assessment of HSCT.

  20. Keep your mind off negative things: coping with long-term effects of acute myeloid leukemia (AML).

    PubMed

    Ghodraty-Jabloo, Vida; Alibhai, Shabbir M H; Breunis, Henriette; Puts, Martine T E

    2016-05-01

    Acute myeloid leukemia (AML) is characterized by sudden onset, intensive treatment, a poor prognosis, and significant relapse risk. Quality of life (QOL) and well-being among AML survivors have been extensively studied during the 6 months of active treatment. However, it is not clear what survivors experience after active treatment. The purpose of our study was to explore how AML survivors describe their longer-term physical and psychosocial well-being and how they cope with these challenges. We conducted a prospective qualitative study and interviewed 19 adult participants (11 had completed treatment, 8 were receiving maintenance chemotherapy). Data were collected using semi-structured interviews that were audio-recorded and transcribed verbatim. The grounded theory approach was used for data analysis. A marked improvement in physical health was reported; however, psychosocial well-being was compromised by enduring emotional distress. A range of emotion- and problem-focused coping strategies were reported. Keeping one's mind off negative things through engaging in formal work or informal activities and seeking control were the two most commonly used coping strategies. Seeking social support for reassurance was also common. Problem-focused strategies were frequently described by the ongoing treatment group to manage treatment side effects. Although physical symptoms improved after completion of treatment, psychosocial distress persisted over longer period of time. In addition, essential needs of AML survivors shifted across survivorship as psychological burden gradually displaced physical concerns. The integral role of coping mechanisms in the adaptation process suggests a need for effective and ongoing psychological interventions.

  1. Phase I Trial of Maintenance Sorafenib after Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-ITD AML

    PubMed Central

    Chen, Yi-Bin; Li, Shuli; Lane, Andrew A.; Connolly, Christine; Del Rio, Candice; Valles, Betsy; Curtis, Morgan; Ballen, Karen; Cutler, Corey; Dey, Bimalangshu R.; El-Jawahri, Areej; Fathi, Amir T.; Ho, Vincent T.; Joyce, Amy; McAfee, Steven; Rudek, Michelle; Rajkhowa, Trivikram; Verselis, Sigitas; Antin, Joseph H.; Spitzer, Thomas R.; Levis, Mark; Soiffer, Robert

    2014-01-01

    The FLT3-ITD mutation is associated with a high relapse rate for patients with AML even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.gov NCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3+3 cohort design was used to define the maximum tolerated dose (MTD) with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT continued for twelve 28-day cycles. Twenty-two patients were enrolled (status at HSCT: CR1=16, CR2=3, refractory=3). The MTD was established at 400 mg BID with one DLT observed (pericardial effusion). Two patients died of transplant-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped due to attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1–35.0). There was one case of grade II acute GVHD after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% CI, 21%–56%). For all patients, one-year progression-free survival (PFS) is 85% (90% CI, 66%–94%) and one-year overall survival (OS) is 95% (90% CI, 79%–99%) after HSCT. For patients in CR1 / CR2 prior to HSCT (n=19), one-year PFS is 95% (90% CI, 76%–99%) and one-year OS is 100% with only one patient who has relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse. PMID:25239228

  2. NPM1, FLT3 and CEBPA mutations in pediatric patients with AML from Argentina: incidence and prognostic value.

    PubMed

    Rubio, Patricia; Campos, B; Digiorge, J A; Gallego, M S; Medina, A; Rossi, J G; Felice, M S; Alonso, C N

    2016-11-01

    Mutations in NPM1, FLT3 and CEBPA genes are found in 25-35 % of adult acute myeloblastic leukemia (AML) cases and correlate with prognosis. To date, there have been no reports about these mutations in pediatric AML from Argentina. The aims of the present study were to describe the incidence of NPM1, FLT3 and CEBPA mutations and to analyze their prognostic impact in this population. The incidences of these mutations within a population of 216 pediatric AML cases were: NPM1-mutated 4.2 %, CEBPA-mutated 1.9 %, FLT3-ITD 10.2 % and FLT3-TKD 7.9 %. Among 33 patients with normal karyotype, we found significantly higher frequencies for NPM1-mutated 24.2 % and CEBPA-mutated 12.1 %. Overall survival (pOS) for the 163 eligible non-acute promyelocytic leukemia cases was 46.2 ± 4.3 %, while leukemia-free survival probability was 51.0 ± 4.4 % (n = 135). The NPM1-mutated/FLT3-ITD-negative genotype showed better outcome than any other combined NPM1/FLT3 genotype; this difference was statistically significant within the group of high-risk patients (pOS ± SE 83.3 ± 15.2 % versus 33.1 ± 4.7 %; p = 0.0251). This is the first report of the frequencies of these mutations in Argentina. Despite the limited number of patients, a favorable prognosis of AML with genotype NPM1-mutated/FLT3-ITD-negative was confirmed. This is especially relevant within the high-risk group of patients, as it may contribute to the detection of patients with better prognosis, and thus avoid unnecessary treatment intensification.

  3. High affinity FRβ-specific CAR T cells eradicate AML and normal yeloid lineage without HSC toxicity

    PubMed Central

    Lynn, Rachel C; Feng, Yang; Schutsky, Keith; Poussin, Mathilde; Kalota, Anna; Dimitrov, Dimiter S; Powell, Daniel J

    2016-01-01

    Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here, we isolated a high affinity (HA) folate receptor beta (FRβ)-specific scFv (2.48nM KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T-cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ+ AML in vitro and in vivo compared to a low affinity (LA) FRβ CAR (54.3nM KD). Using the HA-FRβ IgG, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34+ hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T-cells lysed mature CD14+ monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T-cells retained effective anti-tumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T-cells is highly effective against AML and reduces the risk for long-term myeloid toxicity. PMID:26898190

  4. Efficacy of the Hypomethylating Agents as Frontline, Salvage or Consolidation Therapy in Adults with Acute Myeloid Leukemia (AML)

    PubMed Central

    Tawfik, Bernard; Sliesoraitis, Sarunas; Lyerly, Susan; Klepin, Heidi D.; Lawrence, Julia; Isom, Scott; Ellis, Leslie R.; Manuel, Megan; Dralle, Sarah; Berenzon, Dmitriy; Powell, Bayard L.; Pardee, Timothy

    2013-01-01

    Background The hypomethylating agents (HA), azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with AML. Little is known about how AML responds to hypomethylating agents after standard therapy and the activity of these agents in a real world setting is not well studied. Methods We retrospectively examined data for 75 consecutive AML patients at Wake Forest from 2002–2011 treated with HAs either as 1st line (n=34), salvage (n=28) or consolidation (n=13). We collected data on age, gender, race, Charlson Comorbidity index (CCI), cytogenetics, type of treatment, Complete Remission (CR), Complete Remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan-Meier estimates and cox proportional hazards models. Results Frontline response rate (CR+CRi) was 26.5%, median overall survival (OS) was 3.4 (95% CI 1.3–7.4) months, with 18% alive at one year. In the salvage cohort, the response rate was significantly lower compared to frontline (3.6% versus 26.5%, p=0.017). Despite the reduced response, OS from time of HA treatment was longer than frontline at 8.2 (CI 4.8–10.3) months. In the consolidation cohort OS was 13.8 (CI 8.0 – 21.6) months with one patient in remission more than 30 months from diagnosis. Conclusion These data suggest prior cytotoxic therapy decrease marrow response rates to HAs but not survival. Furthermore, use of hypomethylating agents for consolidation resulted in a median overall survival over one year in a cohort of older patients. This suggests that hypomethylating agents have activity in all phases of AML treatment. PMID:24149914

  5. Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML).

    PubMed

    Tawfik, Bernard; Sliesoraitis, Sarunas; Lyerly, Susan; Klepin, Heidi D; Lawrence, Julia; Isom, Scott; Ellis, Leslie R; Manuel, Megan; Dralle, Sarah; Berenzon, Dmitriy; Powell, Bayard L; Pardee, Timothy

    2014-01-01

    The hypomethylating agents (HAs), azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with acute myeloid leukemia (AML). Little is known about how AML responds to hypomethylating agents after standard therapy, and the activity of these agents in a real-world setting is not well studied. We retrospectively examined data for 75 consecutive AML patients at Wake Forest from 2002 to 2011 treated with HAs either as first-line (n = 34), salvage (n = 28), or consolidation (n = 13) therapy. We collected data on age, gender, race, Charlson comorbidity index (CCI), cytogenetics, type of treatment, complete remission (CR), complete remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan-Meier estimates and Cox proportional hazards models. Frontline response rate (CR + CRi) was 26.5 %, and median overall survival (OS) was 3.4 months (95 % CI 1.3-7.4), with 18 % alive at 1 year. In the salvage cohort, the response rate was significantly lower compared to frontline (3.6 versus 26.5 %, p = 0.017). Despite the reduced response, OS from time of HA treatment was longer than frontline at 8.2 months (CI 4.8-10.3). In the consolidation cohort, OS was 13.8 months (CI 8.0-21.6) with one patient in remission more than 30 months from diagnosis. These data suggest that prior cytotoxic therapy decreases marrow response rates to HAs but not survival. Furthermore, use of hypomethylating agents for consolidation resulted in a median overall survival over 1 year in a cohort of older patients. This suggests that hypomethylating agents have activity in all phases of AML treatment.

  6. FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML

    PubMed Central

    Li, Yumeng; Braun, Thomas; Chang, Lawrence; Bixby, Dale; Hanauer, David A.; Chughtai, Komal A.; Gatza, Erin; Couriel, Daniel; Goldstein, Steven; Pawarode, Attaphol; Reddy, Pavan; Riwes, Mary; Connelly, James; Harris, Andrew; Kitko, Carrie; Levine, John; Yanik, Greg

    2015-01-01

    Allogeneic HCT has been increasingly used in the setting of FLT3 mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein, we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD mutational testing. FLT3 mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs. 37%, P<0.001), and with a shorter median time to relapse (100 vs. 121 days). FLT3 mutational status remained significantly associated with this outcome after controlling for patient, disease, and transplant-related risk factors (P<0.05). Multivariate analysis showed a significant association of FLT3 mutation with increased 3-year RR (HR 3.63, 95% CI: 2.13, 6.19, P<0.001), and inferior disease-free survival (HR 2.05, 95% CI: 1.29, 3.27, P<0.01) and overall survival (HR 1.92, 95% CI: 1.14, 3.24, P<0.05). These data demonstrate high risk of early relapse after allogeneic HCT for FLT3 mutated AML that translates into adverse disease-free and overall survival outcomes. Additional targeted and coordinated interventions are needed to maintain durable remission after allogeneic HCT in this high-risk population. PMID:26191952

  7. Petrography and geochemistry of Ilıca-Şamlı Pluton, NW Turkey

    NASA Astrophysics Data System (ADS)

    Aydın, Halil Can; Özdamar, Şenel

    2017-04-01

    The major and trace elements of the plutonic rocks from the Ilıca-Şamlı Pluton, Northwest of Turkey, were studied to understand petrogenesis. The plutonic rocks consist of a variety of rock types ranging from diorite to granodiorite. Diorites and granodiorite contain large, massive alkali feldspar crystals which are porphyritic textures. These plutonic rocks have SiO2=62-65, Al2O3=14,55-15,74, Fe2O3=4,03-5,85, MgO=1,85-2,80, CaO=4,83-5,96, Na2O=3,14-3.58, K2O=3,04-4,16 major oxide percentages. All of the rocks show a calc-alkaline afinity. Chondrite-normalized REE patterns are moderately fractionated and relatively flat. They display small negative Eu anomalies with enrichment of LILE and less amount of depletion of HFSE. The 40Ar/39Ar ages ˜21-22 Ma. These ages are interpreted as crystalliczation ages of the plutonic rocks and also these ages imply collision of the Intra-Pontide Suture and Anatolide-Tauride platform.

  8. Low-dose salinomycin induces anti-leukemic responses in AML and MLL

    PubMed Central

    Kettyle, Laura M.J.; Matchett, Kyle B.; Keenan, Heather L.; Mulgrew, Nuala M.; Ramsey, Joanne M.; Dougan, Caoifa; McKiernan, John; Grishagin, Ivan V.; Mills, Ken I.; Thompson, Alexander

    2016-01-01

    Development of anti-cancer drugs towards clinical application is costly and inefficient. Large screens of drugs, efficacious for non-cancer disease, are currently being used to identify candidates for repurposing based on their anti-cancer properties. Here, we show that low-dose salinomycin, a coccidiostat ionophore previously identified in a breast cancer screen, has anti-leukemic efficacy. AML and MLLr cell lines, primary cells and patient samples were sensitive to submicromolar salinomycin. Most strikingly, colony formation of normal hematopoietic cells was unaffected by salinomycin, demonstrating a lack of hemotoxicity at the effective concentrations. Furthermore, salinomycin treatment of primary cells resulted in loss of leukemia repopulation ability following transplantation, as demonstrated by extended recipient survival compared to controls. Bioinformatic analysis of a 17-gene signature identified and validated in primary MLLr cells, uncovered immunomodulatory pathways, hubs and protein interactions as potential transducers of low dose salinomycin treatment. Additionally, increased protein expression of p62/Sqstm1, encoded for by one of the 17 signature genes, demonstrates a role for salinomycin in aggresome/vesicle formation indicative of an autophagic response. Together, the data support the efficacy of salinomycin as an anti-leukemic at non-hemotoxic concentrations. Further investigation alone or in combination with other therapies is warranted for future clinical trial. PMID:27612428

  9. Low-dose salinomycin induces anti-leukemic responses in AML and MLL.

    PubMed

    Roulston, Gary D R; Burt, Charlotte L; Kettyle, Laura M J; Matchett, Kyle B; Keenan, Heather L; Mulgrew, Nuala M; Ramsey, Joanne M; Dougan, Caoifa; McKiernan, John; Grishagin, Ivan V; Mills, Ken I; Thompson, Alexander

    2016-11-08

    Development of anti-cancer drugs towards clinical application is costly and inefficient. Large screens of drugs, efficacious for non-cancer disease, are currently being used to identify candidates for repurposing based on their anti-cancer properties. Here, we show that low-dose salinomycin, a coccidiostat ionophore previously identified in a breast cancer screen, has anti-leukemic efficacy. AML and MLLr cell lines, primary cells and patient samples were sensitive to submicromolar salinomycin. Most strikingly, colony formation of normal hematopoietic cells was unaffected by salinomycin, demonstrating a lack of hemotoxicity at the effective concentrations. Furthermore, salinomycin treatment of primary cells resulted in loss of leukemia repopulation ability following transplantation, as demonstrated by extended recipient survival compared to controls. Bioinformatic analysis of a 17-gene signature identified and validated in primary MLLr cells, uncovered immunomodulatory pathways, hubs and protein interactions as potential transducers of low dose salinomycin treatment. Additionally, increased protein expression of p62/Sqstm1, encoded for by one of the 17 signature genes, demonstrates a role for salinomycin in aggresome/vesicle formation indicative of an autophagic response.Together, the data support the efficacy of salinomycin as an anti-leukemic at non-hemotoxic concentrations. Further investigation alone or in combination with other therapies is warranted for future clinical trial.

  10. MiT family translocation renal cell carcinoma.

    PubMed

    Argani, Pedram

    2015-03-01

    The MiT subfamily of transcription factors includes TFE3, TFEB, TFC, and MiTF. Gene fusions involving two of these transcription factors have been identified in renal cell carcinoma (RCC). The Xp11 translocation RCCs were first officially recognized in the 2004 WHO renal tumor classification, and harbor gene fusions involving TFE3. The t(6;11) RCCs harbor a specific Alpha-TFEB gene fusion and were first officially recognized in the 2013 International Society of Urologic Pathology (ISUP) Vancouver classification of renal neoplasia. These two subtypes of translocation RCC have many similarities. Both were initially described in and disproportionately involve young patients, though adult translocation RCC may overall outnumber pediatric cases. Both often have unusual and distinctive morphologies; the Xp11 translocation RCCs frequently have clear cells with papillary architecture and abundant psammomatous bodies, while the t(6;11) RCCs frequently have a biphasic appearance with both large and small epithelioid cells and nodules of basement membrane material. However, the morphology of these two neoplasms can overlap, with one mimicking the other. Both of these RCCs underexpress epithelial immunohistochemical markers like cytokeratin and epithelial membrane antigen (EMA) relative to most other RCCs. Unlike other RCCs, both frequently express the cysteine protease cathepsin k and often express melanocytic markers like HMB45 and Melan A. Finally, TFE3 and TFEB have overlapping functional activity as these two transcription factors frequently heterodimerize and bind to the same targets. Therefore, on the basis of clinical, morphologic, immunohistochemical, and genetic similarities, the 2013 ISUP Vancouver classification of renal neoplasia grouped these two neoplasms together under the heading of "MiT family translocation RCC." This review summarizes our current knowledge of these recently described RCCs. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Plattenepithelkarzinom in Verbindung mit einer roten Tätowierung.

    PubMed

    Schmitz, Inge; Prymak, Oleg; Epple, Matthias; Ernert, Carsten; Tannapfel, Andrea

    2016-06-01

    Obwohl Tätowierungen in den letzten Jahren außerordentlich beliebt geworden sind, wurde in der Literatur bisher nur über wenige Fälle schwerer Reaktionen berichtet, die zu einer malignen Transformation führten. Dies steht im Kontrast zu der praktisch unüberschaubaren Zahl an Tätowierungen weltweit. Die Zusammensetzung der für Tätowierungen verwendeten Farbstoffe variiert stark, und selbst gleiche Farbtöne können unterschiedliche Komponenten enthalten. Das Ziel unserer Studie war es zu untersuchen, auf welche Weise Tätowierungen möglicherweise Hautkrebs auslösen können. Wir berichten über den seltenen Fall einer 24-jährigen Frau, bei der sich sieben Monate nachdem sie eine Tätowierung auf dem Fußrücken erhalten hatte in unmittelbarer Nähe des verwendeten roten Farbstoffs ein Plattenepithelkarzinom entwickelte. Die Komplikationen begannen mit einer unspezifischen Schwellung. Die Läsion wurde histologisch untersucht. Die Zusammensetzung des inkorporierten Farbstoffs wurde mittels Rasterelektronenmikroskopie in Kombination mit energiedispersiver Elementanalyse analysiert. Zur weiteren Charakterisierung wurden Thermogravimetrie und Pulverdiffraktometrie eingesetzt. Der Tätowierungsfarbstoff enthielt hauptsächlich Bariumsulfat; Spuren von Al, S, Ti, P, Mg und Cl ließen sich ebenfalls nachweisen. Bei der Analyse zeigten sich Pigmentgranula unterschiedlicher Größe. In seltenen Fällen kann Tätowierungstinte karzinogene Effekte haben, die multifaktoriell zu sein scheinen. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  12. Technology and human vulnerability. A conversation with MIT's Sherry Turkle.

    PubMed

    Turkle, Sherry

    2003-09-01

    For most of the last 50 years, technology knew its place. Yes, we all spent a lot of time with it, but even five years ago, few people would seriously claim that technology had taken over their lives. It's very different today. Technology is not only ubiquitous but has become highly intrusive as well. On the Internet, people invent imaginary identities in virtual chat rooms, playing out the lives they wish they really lived. Children are growing up with interactive toy animals that respond to them like real pets. Indeed, some critics claim that technology has not just entered our private lives but started to define them. If we want to be sure we'll like who we've become in 50 years, we need to take a closer look at the psychological effects of current and future technologies. The smartest people in technology have already started. Universities like MIT and Caltech have been pouring millions of dollars into researching what happens when technology and humanity meet. To learn more about this research, HBR senior editor Diane L. Coutu spoke with one of the field's most distinguished scholars: Sherry Turkle, MIT's Abby Rockefeller Mauzé Professor in the Program in Science, Technology, and Society and the author of Life on the Screen, which explores how the internet is changing the way we define ourselves. In a conversation with Coutu, Turkle discusses the psychological dynamics that can develop between people and their high-tech toys, describes ways in which machines might substitute for managers, and explains how technology is redefining what it means to be human. She warns that relatively small differences in technology design can have disproportionate effects on how humans relate to technology, to one another, and to themselves.

  13. Low expression of the myeloid differentiation antigen CD65s, a feature of poorly differentiated AML in older adults: study of 711 patients enrolled in ECOG trials.

    PubMed

    Paietta, E; Neuberg, D; Bennett, J M; Dewald, G; Rowe, J M; Cassileth, P A; Cripe, L; Tallman, M S; Wiernik, P H

    2003-08-01

    CD65s appears when the progenitor antigen CD34 disappears, suggesting that this sialylated carbohydrate antigen marks a turning point in normal myeloid differentiation. We characterized acute myeloid leukemia (AML) with low CD65s expression (CD65s(low) AML) in 711 patients entered on seven Eastern Cooperative Oncology Group AML treatment trials (1986-1999). Of those, 198 (28%) qualified as having CD65s(low) AML. Morphologically, CD65s(low) AML was more common in FAB subgroups with minimal differentiation, M0/M1 (P=<0.0001). Early precursor antigens CD34, CD117 and terminal transferase were more frequent in CD65s(low) than CD65s(high) AML (P=<0.0001). Myeloperoxidase was present in fewer CD65s(low) myeloblasts, and the more mature myeloid antigens, CD15 and CD11b, were rarely detected (P=<0.0001). Yet, the two diagnoses did not differ in the distribution of cytogenetic prognostic groups or the occurrence of the multidrug-resistance mediator, P-glycoprotein. CD65s(low) AML patients were significantly older than CD65s(high) cases (P<0.0001). Furthermore, the incidence of CD65s(low) cases increased with age, from 20% in patients under the age of 50 years to 67% in patients older than 80 years (P<0.0001). Overall, complete remission (CR) rate and overall survival were comparable in CD65s(low) and CD65s(high) AML. However, among patients >55 years of age, CD65s(low) AML had a decreased CR rate of 33 vs 44% in CD65s(high) AML (P=0.055). Thus, CD65s(low) AML represents immunophenotypically undifferentiated disease and occurs predominantly in older adults. Although not statistically significant, the observed association between low CD65s expression and decreased CR rate only in patients over the age of 55 is intriguing.

  14. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway.

    PubMed

    Zhang, Yiyun; Wang, Jianfeng; Wheat, Justin; Chen, Xi; Jin, Shan; Sadrzadeh, Hossein; Fathi, Amir T; Peterson, Randall T; Kung, Andrew L; Sweetser, David A; Yeh, Jing-Ruey Joanna

    2013-06-13

    Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and β-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. Inhibition of COX suppresses β-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of β-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/β-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.

  15. RIC versus MAC UCBT in adults with AML: A report from Eurocord, the ALWP and the CTIWP of the EBMT

    PubMed Central

    Beohou, Eric; Labopin, Myriam; Sanz, Guillermo; Milpied, Noel; Michallet, Mauricette; Bacigalupo, Andrea; Blaise, Didier; Sierra, Jorge; Socié, Gérard; Cornelissen, Jan J.; Schmid, Christoph; Giebel, Sebastian; Gorin, Norbert-Claude; Esteve, Jordi; Ciceri, Fabio; Savani, Bipin N.; Mohty, Mohamad; Gluckman, Eliane; Nagler, Arnon

    2016-01-01

    Nonrelapse mortality (NRM) is the first cause of treatment failure after unrelated cord blood transplantation (UCBT) following myeloablative conditioning (MAC). In the last decade, reduced-intensity conditioning (RIC) regimens have been developed with the aim of reducing NRM and allowing older patients and those with medical comorbidities to benefit from UCBT. The aim of the current retrospective study was to compare transplantation outcomes of acute myeloid leukemia (AML) patients given UCBT after either RIC or MAC. Data from 894 adults with AML receiving a single or double UCBT as first allograft from 2004 to 2013 at EBMT centers were included in this study. 415 patients were given UCBT after RIC while 479 patients following a MAC. In comparison to MAC recipients, RIC recipients had a similar incidence of neutrophil engraftment and of acute and chronic graft-versus-host disease (GVHD). However, RIC recipients had a higher incidence of disease relapse and a lower NRM, translating to comparable leukemia-free (LFS), GVHD-free, relapse-free survival (GRFS) and overall survival (OS). These observations remained qualitatively similar after adjusting for differences between groups in multivariate analyses. In conclusion, these data suggest that LFS and OS are similar with RIC or with MAC in adults AML patients transplanted with UCBT. These observations could serve as basis for a future prospective randomized study. PMID:27250025

  16. RIC versus MAC UCBT in adults with AML: A report from Eurocord, the ALWP and the CTIWP of the EBMT.

    PubMed

    Baron, Frédéric; Ruggeri, Annalisa; Beohou, Eric; Labopin, Myriam; Sanz, Guillermo; Milpied, Noel; Michallet, Mauricette; Bacigalupo, Andrea; Blaise, Didier; Sierra, Jorge; Socié, Gérard; Cornelissen, Jan J; Schmid, Christoph; Giebel, Sebastian; Gorin, Norbert-Claude; Esteve, Jordi; Ciceri, Fabio; Savani, Bipin N; Mohty, Mohamad; Gluckman, Eliane; Nagler, Arnon

    2016-07-12

    Nonrelapse mortality (NRM) is the first cause of treatment failure after unrelated cord blood transplantation (UCBT) following myeloablative conditioning (MAC). In the last decade, reduced-intensity conditioning (RIC) regimens have been developed with the aim of reducing NRM and allowing older patients and those with medical comorbidities to benefit from UCBT. The aim of the current retrospective study was to compare transplantation outcomes of acute myeloid leukemia (AML) patients given UCBT after either RIC or MAC. Data from 894 adults with AML receiving a single or double UCBT as first allograft from 2004 to 2013 at EBMT centers were included in this study. 415 patients were given UCBT after RIC while 479 patients following a MAC. In comparison to MAC recipients, RIC recipients had a similar incidence of neutrophil engraftment and of acute and chronic graft-versus-host disease (GVHD). However, RIC recipients had a higher incidence of disease relapse and a lower NRM, translating to comparable leukemia-free (LFS), GVHD-free, relapse-free survival (GRFS) and overall survival (OS). These observations remained qualitatively similar after adjusting for differences between groups in multivariate analyses. In conclusion, these data suggest that LFS and OS are similar with RIC or with MAC in adults AML patients transplanted with UCBT. These observations could serve as basis for a future prospective randomized study.

  17. The role of VDR and BIM in potentiation of cytarabine–induced cell death in human AML blasts

    PubMed Central

    Studzinski, George P.

    2016-01-01

    Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently showed that AML cells in established culture treated with cytarabine (AraC) and a differentiation agent combination show enhancement of AraC cytotoxicity. Here we elucidate molecular changes which underlie this observation with focus on AML blasts in primary culture. The cells were treated with AraC at concentrations achievable in clinical settings, and followed by the addition of Doxercalciferol, a vitamin D2 derivative (D2), together with Carnosic acid (CA), a plant-derived antioxidant. Importantly, although AraC is also toxic to normal bone marrow cell population, the enhanced cell kill by D2/CA was limited to malignant blasts. This enhancement of cell death was associated with activation of the monocytic differentiation program as shown by molecular markers, and the increased expression of vitamin D receptor (VDR). Apoptosis elicited by this treatment is caspase-dependent, and the optimal blast killing required the increased expression of the apoptosis regulator Bim. These data suggest that testing of this regimen in the clinic is warranted. PMID:27144333

  18. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML.

    PubMed

    Park, S; Chapuis, N; Bardet, V; Tamburini, J; Gallay, N; Willems, L; Knight, Z A; Shokat, K M; Azar, N; Viguié, F; Ifrah, N; Dreyfus, F; Mayeux, P; Lacombe, C; Bouscary, D

    2008-09-01

    The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways are frequently activated in acute myelogenous leukemia (AML). mTORC1 inhibition with RAD001 induces PI3K/Akt activation and both pathways are activated independently, providing a rationale for dual inhibition of both pathways. PI-103 is a new potent PI3K/Akt and mTOR inhibitor. In human leukemic cell lines and in primary blast cells from AML patients, PI-103 inhibited constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 was essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibited leukemic proliferation, the clonogenicity of leukemic progenitors and induced mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. In contrast, apoptosis was not induced with RAD001 and IC87114 association, which specifically inhibits mTORC1 and p110delta activity, respectively. PI-103 had additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. Interestingly, PI-103 did not induce apoptosis in normal CD34(+) cells and had moderate effects on their clonogenic and proliferative properties. Here, we demonstrate that multitargeted therapy against PI3K/Akt and mTOR with PI-103 may be of therapeutic value in AML.

  19. Induced mitogenic activity in AML-12 mouse hepatocytes exposed to low-dose ultra-wideband electromagnetic radiation.

    PubMed

    Dorsey, W C; Ford, B D; Roane, L; Haynie, D T; Tchounwou, P B

    2005-04-01

    Ultra-wideband (UWB) technology has increased with the use of various civilian and military applications. In the present study, we hypothesized that low-dose UWB electromagnetic radiation (UWBR) could elicit a mitogenic effect in AML-12 mouse hepatocytes, in vitro. To test this hypothesis, we exposed AML-12 mouse hepatocytes, to UWBR in a specially constructed gigahertz transverse electromagnetic mode (GTEM) cell. Cells were exposed to UWBR for 2 h at a temperature of 23 degrees C, a pulse width of 10 ns, a repetition rate of 1 kHz, and field strength of 5-20 kV/m. UWB pulses were triggered by an external pulse generator for UWBR exposure but were not triggered for the sham exposure. We performed an MTT Assay to assess cell viability for UWBR-treated and sham-exposed hepatocytes. Data from viability studies indicated a time-related increase in hepatocytes at time intervals from 8-24 h post exposure. UWBR exerted a statistically significant (p < 0.05) dose-dependent response in cell viability in both serum-treated and serum free medium (SFM) -treated hepatocytes. Western blot analysis of hepatocyte lysates demonstrated that cyclin A protein was induced in hepatocytes, suggesting that increased MTT activity after UWBR exposure was due to cell proliferation. This study indicates that UWBR has a mitogenic effect on AML-12 mouse hepatocytes and implicates a possible role for UWBR in hepatocarcinoma.

  20. [Clinical curative efficacy of inducing remission for the newly diagnosed aged AML patients by chemotherapy with IA and DA regimens].

    PubMed

    Tian, Dong-Hua; Gan, Si-Lin; Xing, Hai-Zhou; Liu, Yan-Fang; Xie, Xin-Sheng; Sun, Hui

    2014-10-01

    This study was aimed to explore the clinical efficacy and toxicity of idarubicin (IA regimen) and daunoru-bicin combined with cytarabine (DA regimen) for treating aged patients with AML as induction chemotherapy. The clinical data of 60 newly diagnosed AML aged patients treated with IA or DA regimen were analyzed retrospectively. IA regimen group included 22 patients (8 male and 14 females with median age of 66 yrs), while the DA regimen group included 38 patients (20 males and 18 females with median age of 64 yrs). The complete remission rate, total effective rate and adverse effects after one chemotherapy course were compared. The results showed that the CR rate in IA regimen group was 63.63%, which was significantly higer than that in DA regimen group (31.58%) (P < 0.05). The total effective rate was 63.63% and 36.84% respectively in IA and DA regimen groups, there was significant difference between the two groups (P < 0.05). Both the hematological and non-hematological adverse effects were observed and no difference was found in the two regimen groups, neither in myelosupression (P > 0.05), the major hematological adverse effects, nor in non-hematological adverse effects (P > 0.05). It is concluded that for aged AML patients, IA regimen can achieve a higher CR rate and higher total effective rate than that in DA regimen without increase of adverse effects after one induction chemotherapy course.

  1. Sharing post-AML consolidation supportive therapy with local centers reduces patient travel burden without compromising outcomes.

    PubMed

    Hershenfeld, Samantha A; Maki, Kimberly; Rothfels, Lana; Murray, Cindy S; Nixon, Shannon; Schimmer, Aaron D; Doherty, Mary C

    2017-08-01

    Acute myeloid leukemia (AML) is frequently treated with induction and consolidation chemotherapy. Consolidation chemotherapy can be delivered on an ambulatory basis, requiring some patients to travel long distances for treatment at specialized centers. We developed a shared care model where patients receive consolidation chemotherapy at a quaternary center, but post-consolidation supportive care at local hospitals. To evaluate the impact of our model on patient travel and outcomes we conducted a retrospective analysis of AML and acute promyelocytic leukemia patients receiving consolidation over four years at our quaternary center. 73 patients received post-consolidation care locally, and 344 at the quaternary center. Gender, age and cytogenetic risk did not significantly differ between groups. Shared care patients saved mean round trip distance of 146.5km±99.6 and time of 96.7min±63.4 compared to travelling to quaternary center. There was no significant difference in overall survival between groups, and no increased hazard of death for shared care patients. 30, 60, and 90day survival from start of consolidation was 98.6%, 97.2%, and 95.9% for shared care and 98.8%, 97.1%, and 95.3% for quaternary center patients. Thus, a model utilizing regional partnerships for AML post-consolidation care reduces travel burden while maintaining safety. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/β-catenin signaling pathway

    PubMed Central

    Zhang, Yiyun; Wang, Jianfeng; Wheat, Justin; Chen, Xi; Jin, Shan; Sadrzadeh, Hossein; Fathi, Amir T.; Peterson, Randall T.; Kung, Andrew L.

    2013-01-01

    Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and β-catenin–dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. Inhibition of COX suppresses β-catenin activation and serial replating of AE+ mouse HSPCs. Genetic knockdown of β-catenin also abrogates the clonogenic growth of AE+ mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/β-catenin–dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments. PMID:23645839

  3. Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML

    PubMed Central

    Gondek, Lukasz P.; Tiu, Ramon; O'Keefe, Christine L.; Sekeres, Mikkael A.; Theil, Karl S.

    2008-01-01

    Using metaphase cytogenetics (MC), chromosomal abnormalities are found in only a proportion of patients with myelodysplastic syndrome (MDS). We hypothesized that with new precise methods more cryptic karyotypic lesions can be uncovered that may show important clinical implications. We have applied 250K single nucleotide polymorphisms (SNP) arrays (SNP-A) to study chromosomal lesions in samples from 174 patients (94 MDS, 33 secondary acute myeloid leukemia [sAML], and 47 myelodysplastic/myeloproliferative disease [MDS/MPD]) and 76 controls. Using SNP-A, aberrations were found in around three-fourths of MDS, MDS/MPD, and sAML (vs 59%, 37%, 53% by MC; in 8% of patients MC was unsuccessful). Previously unrecognized lesions were detected in patients with normal MC and in those with known lesions. Moreover, segmental uniparental disomy (UPD) was found in 20% of MDS, 23% of sAML, and 35% of MDS/MPD patients, a lesion resulting in copy-neutral loss of heterozygosity undetectable by MC. The potential clinical significance of abnormalities detected by SNP-A, but not seen on MC, was demonstrated by their impact on overall survival. UPD involving chromosomes frequently affected by deletions may have prognostic implications similar to the deletions visible by MC. SNP-A–based karyotyping shows superior resolution for chromosomal defects, including UPD. This technique further complements MC to improve clinical prognosis and targeted therapies. PMID:17954704

  4. Segregation of the AML t(7;11)(p15;p15) translocation chromosomes in somatic cell hybrids

    SciTech Connect

    Borrow, J.; Munroe, D.; Housman, D.E.

    1994-09-01

    The t(7;11)(p15;p15) translocation is a recurrent chromosomal abnormality associated predominately with acute myeloid leukemia (AML) FAB M2 and occasionally with other types of AML or CML blast crisis. High resolution banding techniques have previously localized the breakpoints to 7q15.1 and 11p15.5. We have fused t(7;11)(p15;p15) blast cells from an AML patient to CHTG (hamster) cells in order to segregate the translocated chromosomes from their normal counterparts in somatic cell hybrids. Fusion events containing the derivative chromosomes or the normal chromosome 11 were enriched by panning with the antibodies M1C1 and MER2. These antibodies recognize cell surface markers which are expressed from genes which map to opposite sides of the breakpoint on chromosome 11 (11p13 and 11p15.5, respectively). Individual hybrids were expanded and typed with a series of ordered STSs from chromosomes 7 and 11, and hybrids containing the der(7) and der(11) chromosomes were identified. The segregation of the STSs between the two derivatives is in full agreement with the consensus breakpoint positions as determined cytogenetically. These hybrids may prove useful in further delineation of the breakpoint regions on chromosomes 7 and 11.

  5. Theoretical and experimental study of DOA estimation using AML algorithm for an isotropic and non-isotropic 3D array

    NASA Astrophysics Data System (ADS)

    Asgari, Shadnaz; Ali, Andreas M.; Collier, Travis C.; Yao, Yuan; Hudson, Ralph E.; Yao, Kung; Taylor, Charles E.

    2007-09-01

    The focus of most direction-of-arrival (DOA) estimation problems has been based mainly on a two-dimensional (2D) scenario where we only need to estimate the azimuth angle. But in various practical situations we have to deal with a three-dimensional scenario. The importance of being able to estimate both azimuth and elevation angles with high accuracy and low complexity is of interest. We present the theoretical and the practical issues of DOA estimation using the Approximate-Maximum-Likelihood (AML) algorithm in a 3D scenario. We show that the performance of the proposed 3D AML algorithm converges to the Cramer-Rao Bound. We use the concept of an isotropic array to reduce the complexity of the proposed algorithm by advocating a decoupled 3D version. We also explore a modified version of the decoupled 3D AML algorithm which can be used for DOA estimation with non-isotropic arrays. Various numerical results are presented. We use two acoustic arrays each consisting of 8 microphones to do some field measurements. The processing of the measured data from the acoustic arrays for different azimuth and elevation angles confirms the effectiveness of the proposed methods.

  6. Induced Mitogenic Activity in AML-12 Mouse Hepatocytes Exposed to Low-dose Ultra-Wideband Electromagnetic Radiation

    PubMed Central

    Dorsey, W. C.; Ford, B. D.; Roane, L.; Haynie, D. T.; Tchounwou, P. B.

    2005-01-01

    Ultra–wideband (UWB) technology has increased with the use of various civilian and military applications. In the present study, we hypothesized that low-dose UWB electromagnetic radiation (UWBR) could elicit a mitogenic effect in AML-12 mouse hepatocytes, in vitro. To test this hypothesis, we exposed AML-12 mouse hepatocytes, to UWBR in a specially constructed gigahertz transverse electromagnetic mode (GTEM) cell. Cells were exposed to UWBR for 2 h at a temperature of 23°C, a pulse width of 10 ns, a repetition rate of 1 kHz, and field strength of 5–20 kV/m. UWB pulses were triggered by an external pulse generator for UWBR exposure but were not triggered for the sham exposure. We performed an MTT Assay to assess cell viability for UWBR-treated and sham-exposed hepatocytes. Data from viability studies indicated a time-related increase in hepatocytes at time intervals from 8–24 h post exposure. UWBR exerted a statistically significant (p < 0.05) dose-dependent response in cell viability in both serum-treated and serum free medium (SFM) -treated hepatocytes. Western blot analysis of hepatocyte lysates demonstrated that cyclin A protein was induced in hepatocytes, suggesting that increased MTT activity after UWBR exposure was due to cell proliferation. This study indicates that UWBR has a mitogenic effect on AML-12 mouse hepatocytes and implicates a possible role for UWBR in hepatocarcinoma. PMID:16705798

  7. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia.

    PubMed

    Pession, Andrea; Masetti, Riccardo; Rizzari, Carmelo; Putti, Maria Caterina; Casale, Fiorina; Fagioli, Franca; Luciani, Matteo; Lo Nigro, Luca; Menna, Giuseppe; Micalizzi, Concetta; Santoro, Nicola; Testi, Anna Maria; Zecca, Marco; Biondi, Andrea; Pigazzi, Martina; Rutella, Sergio; Rondelli, Roberto; Basso, Giuseppe; Locatelli, Franco

    2013-07-11

    We evaluated the outcome of 482 children with acute myeloid leukemia (AML) enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 trial. Treatment was stratified according to risk group; hematopoietic stem cell transplantation (HSCT) was used in high-risk (HR) children. Patients with core binding factor leukemia achieving complete remission (CR) after the first induction course were considered standard risk (SR; 99 patients), whereas the others (n = 383) were assigned to the HR group. Allogeneic (ALLO) or autologous (AUTO) HSCT was employed, respectively, in 141 and 102 HR patients after consolidation therapy. CR, early death, and induction failure rates were 87%, 3%, and 10%, respectively. Relapse occurred in 24% of patients achieving CR. The 8-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 68%, 55%, and 63%, respectively. OS, EFS, and DFS for SR and HR patients were 83%, 63%, and 66% and 64%, 53%, and 62%. DFS was 63% and 73% for HR patients given AUTO-HSCT and ALLO-HSCT, respectively. In multivariate analysis, risk group, white blood cell >100 × 10(9)/L at diagnosis, and monosomal karyotype predicted poorer EFS. Risk-oriented treatment and broad use of HSCT result in a long-term EFS comparing favorably with previously published studies on childhood AML.

  8. Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5.

    PubMed

    Carter, Bing Z; Mak, Duncan H; Schober, Wendy D; Dietrich, Martin F; Pinilla, Clemencia; Vassilev, Lyubomir T; Reed, John C; Andreeff, Michael

    2008-04-01

    Acute myeloid leukemia (AML) cells are relatively resistant to tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL). We previously reported that triptolide, a potent anticancer agent from a Chinese herb, decreases XIAP in leukemic cells. We evaluated the combination of triptolide and TRAIL and found synergistic promotion of apoptosis in AML cells. XIAP-overexpressing U937 cells (U937XIAP) were more resistant to TRAIL than U937neo cells, and inhibition of XIAP with the small-molecule inhibitor 1396-11 enhanced TRAIL-induced apoptosis, implying XIAP as a resistance factor in AML. Furthermore, triptolide increased DR5 levels in OCI-AML3, while the DR5 increase was blunted in p53-knockdown OCI-AML3 and p53-mutated U937 cells, confirming a role for p53 in the regulation of DR5. In support of this finding, disruption of MDM2-p53 binding with subsequent increase in p53 levels by nutlin3a increased DR5 levels and sensitized OCI-AML3 cells to TRAIL. The combination of 1396-11 plus nutlin3a plus TRAIL was more effective than either the 1396-11 and TRAIL or nutlin3a and TRAIL combinations in OCI-AML3 cells, further supporting the role of triptolide as a sensitizer to TRAIL-induced apoptosis in part by independent modulation of XIAP expression and p53 signaling. Thus, the combination of triptolide and TRAIL may provide a novel strategy for treating AML by overcoming critical mechanisms of apoptosis resistance.

  9. Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations.

    PubMed

    Bacher, Ulrike; Haferlach, Torsten; Alpermann, Tamara; Zenger, Melanie; Hochhaus, Andreas; Beelen, Dietrich W; Uppenkamp, Michael; Rummel, Mathias; Kern, Wolfgang; Schnittger, Susanne; Haferlach, Claudia

    2011-03-01

    In AML, cooperation of mutations suppressing differentiation ('class-II-mutations') with 'class-I-mutations' increasing cell proliferation is frequent. In rare cases of myeloid malignancies, the BCR-ABL1 fusion was reported to cooperate as class-I-mutation with class-II-mutations, but most cases had to be classified as blast phase of chronic myeloid leukaemia (CML). We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions: 1:220 patients with inv(16)/CBFB-MYH11 (0·5%), 2:272 AML cases with t(8;21)/RUNX1-RUNX1T1 (0·7%), 1:1029 NPM1-mutated AML (0·1%), and one patient with s-AML following MDS with a 5q-deletion. Four patients had m-BCR (e1a2) BCR-ABL1 transcripts; one case only had an M-BCR (b3a2) breakpoint. These cases allow some interesting conclusions: The BCR-ABL1 rearrangement apparently can cooperate with the NPM1 mutation similar to other class-I-mutations. The identification of Philadelphia positive subclones in <1% of patients with CBF-leukaemias fits well with previous observations that most CBF-AML are accompanied by activating mutations in genes enhancing proliferation. Since we observed the occurrence of the Philadelphia positive subclones at diagnosis, at relapse, or throughout the disease, the time point of the emergence of Philadelphia subclones seems variable in AML. Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact.

  10. CD8(+)T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients.

    PubMed

    Wang, Mengjie; Bu, Jin; Zhou, Maohua; Sido, Jessica; Lin, Yu; Liu, Guanfang; Lin, Qiwen; Xu, Xiuzhang; Leavenworth, Jianmei W; Shen, Erxia

    2017-09-08

    Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti-leukemia CD8(+)T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these inhibitory receptors in T cells from AML patients have not been clearly defined. Here we have defined subsets of CD8(+) and CD4(+) T cells in the peripheral blood (PB) from newly diagnosed AML patients and healthy controls (HCs). We have observed increased frequencies of PD-1- and TIGIT expressing CD8(+) T cells but decreased occurrence of CD226-expressing CD8(+)T cells in AML patients. Further analysis of these CD8(+) T cells revealed a unique CD8(+) T cell subset that expressed PD-1 and TIGIT but displayed lower levels of CD226 was associated with failure to achieve remission after induction chemotherapy and FLT3-ITD mutations which predict poor clinical prognosis in AML patients. Importantly, these PD-1(+)TIGIT(+)CD226(-)CD8(+)T cells are dysfunctional with lower expression of intracellular IFN-γ and TNF-α than their counterparts in HCs. Therefore, our studies revealed that an increased frequency of a unique CD8(+) T cell subset, PD-1(+)TIGIT(+)CD226(-)CD8(+) T cells, is associated with CD8(+)T cell dysfunction and poor clinical prognosis of AML patients, which may reveal critical diagnostic or prognostic biomarkers and direct more efficient therapeutic strategies. Copyright © 2017. Published by Elsevier Inc.

  11. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells.

    PubMed

    Fiskus, W; Sharma, S; Saha, S; Shah, B; Devaraj, S G T; Sun, B; Horrigan, S; Leveque, C; Zu, Y; Iyer, S; Bhalla, K N

    2015-06-01

    The canonical wingless-type MMTV integration site (WNT)-β-catenin pathway is essential for self-renewal, growth and survival of acute myeloid leukemia (AML) stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of β-catenin, causing increased nuclear translocation and co-factor activity of β-catenin with the transcriptional regulator T-cell factor (TCF) 4/lymphoid enhancer factor 1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate β-catenin levels. BC treatment disrupted the binding of β-catenin with the scaffold protein transducin β-like 1 and proteasomal degradation and decline in the nuclear levels of β-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-MYC and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs, exhibiting nuclear expression of β-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD.

  12. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: Synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors, and JAK inhibitors

    PubMed Central

    Weisberg, Ellen; Liu, Qingsong; Nelson, Erik; Kung, Andrew L.; Christie, Amanda L.; Bronson, Rod; Sattler, Martin; Sanda, Takaomi; Zhao, Zheng; Hur, Wooyoung; Mitsiades, Constantine; Smith, Robert; Daley, John F.; Stone, Richard; Galinsky, Ilene; Griffin, James D.; Gray, Nathanael

    2014-01-01

    Acute myeloid leukemia (AML) progenitors are frequently characterized by activating mutations in the receptor tyrosine kinase FLT3. Protein tyrosine kinases are integral components of signaling cascades that play a role in both FLT3-mediated transformation as well as viability pathways that are advantageous to leukemic cell survival. The bone marrow microenvironment can diminish AML sensitivity to tyrosine kinase inhibitors (TKIs). We hypothesized that inhibition of protein kinases in addition to FLT3 may be effective in overriding drug resistance in AML. We used a cell-based model mimicking stromal protection as part of an unbiased high-throughput chemical screen to identify kinase inhibitors with the potential to override microenvironment-mediated drug resistance in mutant FLT3-positive AML. Several related multi-targeted kinase inhibitors, including dasatinib, with the capability of reversing microenvironment-induced resistance to FLT3 inhibition were identified and validated. We validated synergy in vitro and demonstrated effective combination potential in vivo. In particular Janus kinase (JAK) inhibitors were effective in overriding stromal protection and potentiating FLT3 inhibition in primary AML and cell lines. These results hint at a novel concept of using combination therapy to override drug resistance in mutant FLT3-positive AML in the bone marrow niche and suppress or eradicate residual disease. PMID:22469781

  13. Detectable FLT3-ITD or RAS mutation at the time of transformation from MDS to AML predicts for very poor outcomes

    PubMed Central

    Badar, Talha; Patel, Keyur P; Thompson, Philip A; DiNardo, Courtney; Takahashi, Koichi; Cabrero, Monica; Borthakur, Gautam; Cortes, Jorge; Konopleva, Marina; Kadia, Tapan; Bohannan, Zach; Pierce, Sherry; Jabbour, Elias J; Ravandi, Farhad; Daver, Naval; Luthra, Raja; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2016-01-01

    Background The molecular events that drive the transformation from myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) have yet to be fully characterized. We hypothesized that detection of these mutations at the time of transformation from MDS to AML may lead to poorer outcomes. Methods We analyzed 102 MDS patients who were admitted to our institution between 2004 and 2013, had wild-type (wt) FLT3-ITD and RAS at diagnosis, progressed to AML, and had serial mutation testing at both the MDS and AML stages. Results We detected FLT3-ITD and/or RAS mutations in twenty-seven (26%) patients at the time of transformation to AML. Twenty-two patients (81%) had RAS mutations and five (19%) had FLT3-ITD mutations. The median survival after leukemia transformation in patients who had detectable RAS and/or FLT3-ITD mutations was 2·4 months compared to 7·5 months in patients who retained wt RAS and FLT3-ITD (hazard ratio [HR]: 3·08, 95% confidence interval [CI]: 1·9–5·0, p < 0·0001). In multivariate analysis, FLT3-ITD and RAS mutations had independent prognostic significance for poor outcome. Conclusions We conclude that 26% of patients had detectable FLT3-ITD or RAS mutation at transformation to AML, and these mutations were associated with very poor outcome. PMID:26547258

  14. Homoharringtonine combined with aclarubicin and cytarabine synergistically induces apoptosis in t(8;21) leukemia cells and triggers caspase-3-mediated cleavage of the AML1-ETO oncoprotein.

    PubMed

    Cao, Jiang; Feng, Hao; Ding, Ning-Ning; Wu, Qing-Yun; Chen, Chong; Niu, Ming-Shan; Chen, Wei; Qiu, Ting-Ting; Zhu, Hong-Hu; Xu, Kai-Lin

    2016-11-01

    Homoharringtonine combined with aclarubicin and cytarabine (HAA) is a highly effective treatment for acute myeloid leukemia (AML), especially for t(8;21) AML. However, the underlying mechanisms by which HAA kills t(8;21) AML cells remain unclear. In this study, SKNO-1 and Kasumi-1 cells with t(8;21) were used. Compared with individual or pairwise administration of homoharringtonine, aclarubicin, or cytarabine, HAA showed the strongest inhibition of growth and induction of apoptosis in SKNO-1 and Kasumi-1 cells. HAA caused cleavage of the AML1-ETO (AE) oncoprotein to form truncated AE (ΔAE). Pretreatment with the caspase-3 inhibitor caspase-3 inhibitor Q-DEVD-OPh (QDO) not only suppressed HAA-induced apoptosis but also abrogated the cleavage of AE and generation of ΔAE. These results suggest that HAA synergistically induces apoptosis in t(8;21) leukemia cells and triggers caspase-3-mediated cleavage of the AML1-ETO oncoprotein, thus providing direct evidence for the strong activity of HAA toward t(8;21) AML.

  15. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML.

    PubMed

    Kung Sutherland, May S; Walter, Roland B; Jeffrey, Scott C; Burke, Patrick J; Yu, Changpu; Kostner, Heather; Stone, Ivan; Ryan, Maureen C; Sussman, Django; Lyon, Robert P; Zeng, Weiping; Harrington, Kimberly H; Klussman, Kerry; Westendorf, Lori; Meyer, David; Bernstein, Irwin D; Senter, Peter D; Benjamin, Dennis R; Drachman, Jonathan G; McEarchern, Julie A

    2013-08-22

    Outcomes in acute myeloid leukemia (AML) remain unsatisfactory, and novel treatments are urgently needed. One strategy explores antibodies and their drug conjugates, particularly those targeting CD33. Emerging data with gemtuzumab ozogamicin (GO) demonstrate target validity and activity in some patients with AML, but efficacy is limited by heterogeneous drug conjugation, linker instability, and a high incidence of multidrug resistance. We describe here the development of SGN-CD33A, a humanized anti-CD33 antibody with engineered cysteines conjugated to a highly potent, synthetic DNA cross-linking pyrrolobenzodiazepine dimer via a protease-cleavable linker. The use of engineered cysteine residues at the sites of drug linker attachment results in a drug loading of approximately 2 pyrrolobenzodiazepine dimers per antibody. In preclinical testing, SGN-CD33A is more potent than GO against a panel of AML cell lines and primary AML cells in vitro and in xenotransplantation studies in mice. Unlike GO, antileukemic activity is observed with SGN-CD33A in AML models with the multidrug-resistant phenotype. Mechanistic studies indicate that the cytotoxic effects of SGN-CD33A involve DNA damage with ensuing cell cycle arrest and apoptotic cell death. Together, these data suggest that SGN-CD33A has CD33-directed antitumor activity and support clinical testing of this novel therapeutic in patients with AML.

  16. Evaluation of the MIT RMID 1000 system for the identification of Listeria species.

    PubMed

    Ricardi, John; Haavig, David; Cruz, Lasaunta; Paoli, George; Gehring, Andrew

    2010-01-01

    The Micro Imaging Technology (MIT) 1000 Rapid Microbial Identification (RMID) System is a device that uses the principles of light scattering coupled with proprietary algorithms to identify bacteria after being cultured and placed in a vial of filtered water. This specific method is for pure culture identification of Listeria spp. A total of 81 microorganisms (55 isolates) were tested by the MIT 1000 System, of which 25 were Listeria spp. and 30 a variety of other bacterial species. In addition, a total of 406 tests over seven different ruggedness parameters were tested by the MIT 1000 System to determine its flexibility to the specifications stated in the MIT 1000 System User Guide in areas where they might be deviated by a user to shorten the test cycle. Overall, MIT concluded that the MIT 1000 System had an accuracy performance that should certify this Performance Test Method for the identification of Listeria spp. This report discusses the tests performed, results achieved, and conclusions, along with several reference documents to enable a higher understanding of the technology used by the MIT 1000 System.

  17. Having Fun with Physics at the MIT Plasma Science and Fusion Center

    NASA Astrophysics Data System (ADS)

    Rivenberg, P.; Thomas, P.; Censabella, V.; Granville, J.; Nachtrieb, R.; Gangadhara, S.

    1997-11-01

    MIT Plasma Science and Fusion Center staff and students are convinced that students learn best not by studying but by doing. This was the impetus behind a group of MIT graduate students who created Cambridge Physics Outlet, a PSFC spin-off company dedicated to creating hands-on experiments. The same impulse fostered the award-winning Mr. Magnet Program, a traveling presentation which uses a hands-on strategy to engage elementary school children. A number of ingenious experiments will be demonstrated. The PSFC maintains a Home Page on the World Wide Web, which can be reached at HTTP://PFC.MIT.EDU.

  18. Segmentierung des Femurs aus MRT-Daten mit Shape-Based Level-Sets

    NASA Astrophysics Data System (ADS)

    Dekomien, Claudia; Busch, Martin; Teske, Wolfram; Winter, Susanne

    Inhalt dieser Arbeit ist die Segmentierung des Femurs aus MRT-Datensätzen mit einem Shape-based Level-Set-Ansatz. Der Algorithmus besteht aus zwei Phasen, der Modellerstellung und der Segmentierungsphase. In der Segmentierungsphase wurde ein kantenbasiertes und ein auf Intensitäten basierendes Optimierungskriterium mit einander kombiniert. Für eine lokale Verbesserung des Ergebnisses wurde zusätzlich ein Laplacian Level-Set-Verfahren angewendet. Der Femur konnte mit diesem Ansatz in drei verschiedenen MRT-Sequenzen und einem Fusionsdatensatz gut segmentiert werden.

  19. Utility of the M.I.T. (Massachusetts Institute of Technology) Underwater Stud Welding Gun.

    DTIC Science & Technology

    1984-06-01

    MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE, MASSACHUSETTS 02139 UTILITY OF THE MIT U-A.RWATER STUD WELDING ; GUN ~{VRY ~iPR>UfIT, JR. JLieuLk2fillL U...zv ~ :(X.~ML)Course 1 3A N ’T unle 1984 .................... A.r " 1- My Ms 31cmmWffi.ZL UTILITY OF THE M.I.T. UNDERWATER STUD WELDING GUN by...A Accession For NTIS GRA&I e.. DTIC TAB UTILITY OF THE M.I.T. Dist" " UNDERWATER STUD WELDING GUN Dist I - "-by I !- Henry Lowe Pruitt, Jr

  20. Star in Deep Freeze Chills Theory, MIT Researchers Report

    NASA Astrophysics Data System (ADS)

    2001-09-01

    CAMBRIDGE, Mass. -- Like a frozen turkey that just won't thaw, a strange star near the center of the Milky Way is surprising MIT experts and colleagues with its remarkably low temperature. The odd behavior is chilling current theories of stellar physics. A famously battered neutron star named KS 1731-260 appears no hotter than some of its tranquil brethren, despite enduring the heat of constant thermonuclear explosions with the force of billions of hydrogen bombs every second across a region only a few miles wide for the past 12 years. Dr. Rudi Wijnands, an astrophysicist at MIT's Center for Space Research, used the Chandra X-ray Observatory to measure the temperature of the neutron star at a very opportune moment, only months after the nuclear war apparently ended and the smoke cleared. He presented his team's findings September 5 in Washington, D.C. at a scientific conference entitled "Two Years of Science with Chandra." "Twelve years of constant thermonuclear explosions: One would think that would heat things up," said Wijnands. "This leaves us wondering whether some neutron stars are in the freezer for a much longer time than previously thought and consequently take a long time to heat up, or whether they cool down incredibly fast. Either explanation has profound implications for our field." Neutron stars are the dense, core remains of stars once many times more massive than our Sun. They are created in dazzling supernovas, in which the outer shell of the star explodes into space, and the core, containing about as much mass as the Sun, implodes and collapses into a sphere no wider than Cambridge, Massachusetts. Despite their tiny size, neutron stars are visible in several ways. One is through accretion. Neutron stars are a strong source of gravity. When they exist in binary star systems, such as KS 1731-260, they can attract the gas from what is often a "healthy" hydrogen-burning companion star (although the nature of KS 1731-260's companion is not clear.) Gas

  1. Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells.

    PubMed

    Han, Lina; Qiu, Peng; Zeng, Zhihong; Jorgensen, Jeffrey L; Mak, Duncan H; Burks, Jared K; Schober, Wendy; McQueen, Teresa J; Cortes, Jorge; Tanner, Scott D; Roboz, Gail J; Kantarjian, Hagop M; Kornblau, Steven M; Guzman, Monica L; Andreeff, Michael; Konopleva, Marina

    2015-04-01

    Understanding the unique phenotypes and complex signaling pathways of leukemia stem cells (LSCs) will provide insights and druggable targets that can be used to eradicate acute myeloid leukemia (AML). Current work on AML LSCs is limited by the number of parameters that conventional flow cytometry (FCM) can analyze because of cell autofluorescence and fluorescent dye spectral overlap. Single-cell mass cytometry (CyTOF) substitutes rare earth elements for fluorophores to label antibodies, which allows measurements of up to 120 parameters in single cells without correction for spectral overlap. The aim of this study was the evaluation of intracellular signaling in antigen-defined stem/progenitor cell subsets in primary AML. CyTOF and conventional FCM yielded comparable results on LSC phenotypes defined by CD45, CD34, CD38, CD123, and CD99. Intracellular phosphoprotein responses to ex vivo cell signaling inhibitors and cytokine stimulation were assessed in myeloid leukemia cell lines and one primary AML sample. CyTOF and conventional FCM results were confirmed by western blotting. In the primary AML sample, we investigated the cell responses to ex vivo stimulation with stem cell factor and BEZ235-induced inhibition of PI3K and identified activation patterns in multiple PI3K downstream signaling pathways including p-4EBP1, p-AKT, and p-S6, particularly in CD34(+) subsets. We evaluated multiple signaling pathways in antigen-defined subpopulations in primary AML cells with FLT3-ITD mutations. The data demonstrated the heterogeneity of cell phenotype distribution and distinct patterns of signaling activation across AML samples and between AML and normal samples. The mTOR targets p-4EBP1 and p-S6 were exclusively found in FLT3-ITD stem/progenitor cells, but not in their normal counterparts, suggesting both as novel targets in FLT3 mutated AML. Our data suggest that CyTOF can identify functional signaling pathways in antigen-defined subpopulations in primary AML, which may

  2. Solution of the inverse problem of magnetic induction tomography (MIT).

    PubMed

    Merwa, Robert; Hollaus, Karl; Brunner, Patricia; Scharfetter, Hermann

    2005-04-01

    Magnetic induction tomography (MIT) of biological tissue is used to reconstruct the changes in the complex conductivity distribution inside an object under investigation. The measurement principle is based on determining the perturbation DeltaB of a primary alternating magnetic field B0, which is coupled from an array of excitation coils to the object under investigation. The corresponding voltages DeltaV and V0 induced in a receiver coil carry the information about the passive electrical properties (i.e. conductivity, permittivity and permeability). The reconstruction of the conductivity distribution requires the solution of a 3D inverse eddy current problem. As in EIT the inverse problem is ill-posed and on this account some regularization scheme has to be applied. We developed an inverse solver based on the Gauss-Newton-one-step method for differential imaging, and we implemented and tested four different regularization schemes: the first and second approaches employ a classical smoothness criterion using the unit matrix and a differential matrix of first order as the regularization matrix. The third method is based on variance uniformization, and the fourth method is based on the truncated singular value decomposition. Reconstructions were carried out with synthetic measurement data generated with a spherical perturbation at different locations within a conducting cylinder. Data were generated on a different mesh and 1% random noise was added. The model contained 16 excitation coils and 32 receiver coils which could be combined pairwise to give 16 planar gradiometers. With 32 receiver coils all regularization methods yield fairly good 3D-images of the modelled changes of the conductivity distribution, and prove the feasibility of difference imaging with MIT. The reconstructed perturbations appear at the right location, and their size is in the expected range. With 16 planar gradiometers an additional spurious feature appears mirrored with respect to the median

  3. Internationalizing Practical ChE Education: The M.I.T. Practice School in Japan.

    ERIC Educational Resources Information Center

    O'Connor, Andrea J.; Kandas, Angelo W.; Natori, Yukikazu; Hatton, T. Alan

    1999-01-01

    Describes the establishment, benefits, and difficulties of an overseas branch of the Massachusetts Institute of Technology's (MIT) chemical engineering Practice School for student internship study at the Mitsubishi Chemical Corporation's Mizushima Plant in Kurashiki, Japan. (WRM)

  4. Impact of loss of BH3-only proteins on the development and treatment of MLL-fusion gene-driven AML in mice

    PubMed Central

    Bilardi, Rebecca A; Anstee, Natasha S; Glaser, Stefan P; Robati, Mikara; Vandenberg, Cassandra J; Cory, Suzanne

    2016-01-01

    Inhibition of the apoptosis pathway controlled by opposing members of the Bcl-2 protein family plays a central role in cancer development and resistance to therapy. To investigate how pro-apoptotic Bcl-2 homology domain 3 (BH3)-only proteins impact on acute myeloid leukemia (AML), we generated mixed lineage leukemia (MLL)-AF9 and MLL-ENL AMLs from BH3-only gene knockout mice. Disease development was not accelerated by loss of Bim, Puma, Noxa, Bmf, or combinations thereof; hence these BH3-only proteins are apparently ineffectual as tumor suppressors in this model. We tested the sensitivity of MLL-AF9 AMLs of each genotype in vitro to standard chemotherapeutic drugs and to the proteasome inhibitor bortezomib, with or without the BH3 mimetic ABT-737. Loss of Puma and/or Noxa increased resistance to cytarabine, daunorubicin and etoposide, while loss of Bim protected against cytarabine and loss of Bmf had no impact. ABT-737 increased sensitivity to the genotoxic drugs but was not dependent on any BH3-only protein tested. The AML lines were very sensitive to bortezomib and loss of Noxa conveyed significant resistance. In vivo, several MLL-AF9 AMLs responded well to daunorubicin and this response was highly dependent on Puma and Noxa but not Bim. Combination therapy with ABT-737 provided little added benefit at the daunorubicin dose trialed. Bortezomib also extended survival of AML-bearing mice, albeit less than daunorubicin. In summary, our genetic studies reveal the importance of Puma and Noxa for the action of genotoxics currently used to treat MLL-driven AML and suggest that, while addition of ABT-737-like BH3 mimetics might enhance their efficacy, new Noxa-like BH3 mimetics targeting Mcl-1 might have greater potential. PMID:27584789

  5. MIT Lincoln Laboratory Annual Report 2008: Technology in Support of National Security

    DTIC Science & Technology

    2008-01-01

    at MIT Lincoln Laboratory MIT news Program spurs students to pursue scientific careers January 4, 2008 Dan Gabriner asks students to solve a...high-school students to pursue careers in science, technology, engineering, and math, Lincoln Laboratory hires local teachers every summer to work...prevents airplanes from crashing into one another while landing.” The long-term goals of LIFT2 are to entice students to pursue a technical career and

  6. MIT Laboratory for Computer Science Progress Report, July 1984-June 1985

    DTIC Science & Technology

    1985-06-01

    34 Office of Naval Research; " United States Air Force; " United States Army Research Office " MIT controlled IBM funds under an IBM/MIT joint study contract...Current Status 127 5. Future Plans 127 6. Resources and Participants 128 PROGRAMMING METHODOLOGY 129 1. Overview . 130 2. Implementation 130 3...include the use of computers in the educational process by the 1 ducational Computing Group; the use of interconnected computers for planning ; as well gs

  7. Echtzeit-Ultraschallsimulation auf Grafik-Prozessoren mit CUDA

    NASA Astrophysics Data System (ADS)

    Reichl, Tobias; Passenger, Josh; Acosta, Oscar; Salvado, Olivier

    Trotz der zunehmenden Verbreitung jüngerer bildgebender Verfahren bleibt medizinischer Ultraschall (US) weiterhin ein wichtiges Hilfsmittel bei chirurgischen Eingriffen und der klinischen Diagnose. Viele US-gestützte medizinische Prozeduren erfordern allerdings ausgiebiges Training, so dass es wünschenswert ist, eine realistische Simulation von US-Bildern zur Verfügung zu stellen. Im Gegensatz zu früheren Ansätzen simulieren wir solche Bilder auf der "Graphics Processing Unit“. Wir erweitern hierzu eine Methode, die von Wein et al. für die Abschätzung von US-Reflexionen aus Daten der Computertomographie (CT) vorgeschlagen wurde, zu einer leichter zu berechnenden Form. Zusätzlich schätzen wir die US-Absorption aus den CT-Daten ab. Mit Hilfe von NVIDIAs "Compute Unified Device Architecture“ (CUDA) simulieren wir Reflexion, Verschattung, Rauschen und radiale Unschärfe, ausgehend von unbearbeiteten CT-Daten in Echtzeit und ohne Vorausberechnung.

  8. Educational Outreach at the MIT