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1

Tfe3 expression is closely associated to macrophage terminal differentiation of human hematopoietic myeloid precursors  

SciTech Connect

The MItf-Tfe family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors encodes four family members: MItf, Tfe3, TfeB and TfeC. In vitro, each protein of the family binds DNA in a homo- or heterodimeric form with other family members. Tfe3 is involved in chromosomal translocations recurrent in different tumors and it has been demonstrated, by in vivo studies, that it plays, redundantly with MItf, an important role in the process of osteoclast formation, in particular during the transition from mono-nucleated to multi-nucleated osteoclasts. Since mono-nucleated osteoclasts derive from macrophages we investigated whether Tfe3 might play a role upstream during hematopoietic differentiation. Here we show that Tfe3 is able to induce mono-macrophagic differentiation of U937 cells, in association with a decrease of cell proliferation and an increase of apoptosis. We also show that Tfe3 does not act physiologically during commitment of CD34+ hematopoietic stem cells (HSCs), since it is not able to direct HSCs toward a specific lineage as observed by clonogenic assay, but is a strong actor of terminal differentiation since it allows human primary myeloblasts' maturation toward the macrophage lineage.

Zanocco-Marani, Tommaso [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Vignudelli, Tatiana [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Gemelli, Claudia [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Pirondi, Sara [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Testa, Anna [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Montanari, Monica [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Parenti, Sandra [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Tenedini, Elena [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Grande, Alexis [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy); Ferrari, Sergio [Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Universita di Modena e Reggio Emilia, Via Campi 287, 41100, Modena (Italy)]. E-mail: sergio@unimo.it

2006-12-10

2

CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors  

PubMed Central

The DNA hypomethylating drug decitabine maintains normal hematopoietic stem cell (HSC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. The basis for these contrasting cell-fates, and for selective CpG hypomethylation by decitabine, is poorly understood. Promoter CpGs, with methylation measured by microarray, were classified by the direction of methylation change with normal myeloid maturation. In AML cells, the methylation pattern at maturation-responsive CpG suggested at least partial maturation. Consistent with partial maturation, in gene expression analyses, AML cells expressed high levels of the key lineage-specifying factor CEBPA, but relatively low levels of the key late-differentiation driver CEBPE. In methylation analysis by mass-spectrometry, CEBPE promoter CpG that are usually hypomethylated during granulocyte maturation were significantly hypermethylated in AML cells. Decitabine treatment induced cellular differentiation of AML cells, and the largest methylation decreases were at CpG that are hypomethylated with myeloid maturation, including CEBPE promoter CpG. In contrast, decitabine-treated normal HSC retained immature morphology, and methylation significantly decreased at CpG that are less methylated in immature cells. High expression of lineage-specifying factor and aberrant epigenetic repression of some key late-differentiation genes distinguishes AML cells from normal HSC and could explain the contrasting differentiation and methylation responses to decitabine.

Negrotto, Soledad; Ng, Kwok Peng; Jankowska, Ania M.; Bodo, Juraj; Gopalan, Banu; Guinta, Kathryn; Mulloy, James C.; Hsi, Eric; Maciejewski, Jaroslaw; Saunthararajah, Yogen

2011-01-01

3

Gene transfer to pre-hematopoietic and committed hematopoietic precursors in the early mouse Yolk Sac: a comparative study between in situ electroporation and retroviral transduction  

PubMed Central

Background Hematopoietic development in vertebrate embryos results from the sequential contribution of two pools of precursors independently generated. While intra-embryonic precursors harbour the features of hematopoietic stem cells (HSC), precursors formed earlier in the yolk sac (YS) display limited differentiation and self-renewal potentials. The mechanisms leading to the generation of the precursors in both sites are still largely unknown, as are the molecular basis underlying their different potential. A possible approach to assess the role of candidate genes is to transfer or modulate their expression/activity in both sites. We thus designed and compared transduction protocols to target either native extra-embryonic precursors, or hematopoietic precursors. Results One transduction protocol involves transient modification of gene expression through in situ electroporation of the prospective blood islands, which allows the evolution of transfected mesodermal cells in their "normal" environment, upon organ culture. Following in situ electroporation of a GFP reporter construct into the YS cavity of embryos at post-streak (mesodermal/pre-hematopoietic precursors) or early somite (hematopoietic precursors) stages, high GFP expression levels as well as a good preservation of cell viability is observed in YS explants. Moreover, the erythro-myeloid progeny typical of the YS arises from GFP+ mesodermal cells or hematopoietic precursors, even if the number of targeted precursors is low. The second approach, based on retroviral transduction allows a very efficient transduction of large precursor numbers, but may only be used to target 8 dpc YS hematopoietic precursors. Again, transduced cells generate a progeny quantitatively and qualitatively similar to that of control YS. Conclusion We thus provide two protocols whose combination may allow a thorough study of both early and late events of hematopoietic development in the murine YS. In situ electroporation constitutes the only possible gene transfer method to transduce mesodermal/pre-hematopoietic precursors and analyze the earliest steps of hematopoietic development. Both in situ electroporation and retroviral transduction may be used to target early hematopoietic precursors, but the latter appears more convenient if a large pool of stably transduced cells is required. We discuss the assets and limitation of both methods, which may be alternatively chosen depending on scientific constraints.

Giroux, Sebastien JD; Alves-Leiva, Celmar; Lecluse, Yann; Martin, Patrick; Albagli, Olivier; Godin, Isabelle

2007-01-01

4

Mapping gene expression patterns during myeloid differentiation using the EML hematopoietic progenitor cell line  

Microsoft Academic Search

ObjectiveThe detailed examination of the molecular events that control the early stages of myeloid differentiation has been hampered by the relative scarcity of hematopoietic stem cells and the lack of suitable cell line models. In this study, we examined the expression of several myeloid and nonmyeloid genes in the murine EML hematopoietic stem cell line.

Yang Du; Janee L Campbell; Demet Nalbant; Hyewon Youn; Ann C. Hughes Bass; Everardo Cobos; Schickwann Tsai; Jonathan R Keller; Simon C Williams

2002-01-01

5

Advances in hematopoietic stem cell transplantation in chronic myeloid leukemia.  

PubMed

Treatment of chronic myeloid leukemia (CML) has evolved dramatically with the development of tyrosine kinase inhibitors (TKIs). This past decade also witnessed major advances in the field of allogeneic hematopoietic stem cell transplantation (alloHSCT) that led to better patients' outcomes. Progress in the exploitation of alternative sources of stem cells, development of novel conditioning regimens, discovery of innovative graft-versus-host prophylactic strategies, and advances in supportive care as well as positioning of alloHSCT in the overall management of CML are discussed in this article. PMID:24099673

Veldman, Rachel; El Rassi, Fuad; Holloway, Stacie; Langston, Amelia; Khoury, Hanna Jean

2013-10-01

6

Hematopoietic stem cell transplantation for patients with chronic myeloid leukemia  

Microsoft Academic Search

Objective  To evaluate the effects of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for patients with chronic\\u000a myeloid leukemia(CML).\\u000a \\u000a \\u000a \\u000a Methods  Fifty-seven patients with CML were treated by HSCT, including 8 cases treated with autologous transplantation purged in vivo\\u000a and in vitro of minimal residual disease (MRD), 39 cases with related donor allogeneic HSCT (allo-HSCT) and 10 cases with\\u000a unrelated donor allo-HSCT.

Qifa Liu; Zhiping Fan; Jing Sun; Yu Zhang; Xiaoli Liu; Dan Xu; Bing Xu; Ru Feng; Fanyi Meng; Shuyun Zhou

2004-01-01

7

Intraembryonic, but not yolk sac hematopoietic precursors, isolated before circulation, provide long-term multilineage reconstitution.  

PubMed

The relative contribution of yolk sac and intraembryonic precursors to hematopoiesis has been a matter of long-standing controversy. As reconstitution activity has so far only been found in embryonic tissues after the onset of circulation, the origin of reconstituting cells could not be formally established. Here, we separated yolk sac and intraembryonic splanchnopleura prior to circulation and maintained the explants in organ culture before transfer. Precursors derived from the intraembryonic site generated multilineage hematopoietic progeny in adult mice for more than 6 months. Yolk sac cells only provided myeloid short-term reconstitution. The results reveal a differential hematopoietic capacity of precirculation embryonic tissues in vivo, and indicate that the only cells capable of adult long-term hematopoiesis are of intraembryonic origin. PMID:11567637

Cumano, A; Ferraz, J C; Klaine, M; Di Santo, J P; Godin, I

2001-09-01

8

The Hematopoietic Differentiation and Production of Mature Myeloid Cells from Human Pluripotent Stem Cells  

PubMed Central

Here we describe a protocol for hematopoietic differentiation of human pluripotent stem cells (hPSCs) and generation of mature myeloid cells from hPSCs through expansion and differentiation of hPSC-derived lin-CD34+CD43+CD45+ multipotent progenitors. The protocol is comprised of three major steps: (i) induction of hematopoietic differentiation by coculture of hPSCs with OP9 bone marrow stromal cells, (ii) short-term expansion of multipotent myeloid progenitors with a high dose of GM-CSF, and (iii) directed differentiation of myeloid progenitors into neutrophils, eosinophils, dendritic cells (DCs), Langerhans cells (LCs), macrophages, and osteoclasts. The generation of multipotent hematopoietic progenitors from hPSCs requires 9 days of culture, and an additional 2 days are needed to expand myeloid progenitors. Differentiation of myeloid progenitors into mature myeloid cells requires an additional 5–19 days of culture with cytokines, depending on the cell type.

Choi, Kyung-Dal; Vodyanik, Maxim; Slukvin, Igor I.

2011-01-01

9

TREM2-Transduced Myeloid Precursors Mediate Nervous Tissue Debris Clearance and Facilitate Recovery in an Animal Model of Multiple Sclerosis  

PubMed Central

Background In multiple sclerosis, inflammation can successfully be prevented, while promoting repair is still a major challenge. Microglial cells, the resident phagocytes of the central nervous system (CNS), are hematopoietic-derived myeloid cells and express the triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor. Myeloid cells are an accessible source for ex vivo gene therapy. We investigated whether myeloid precursor cells genetically modified to express TREM2 affect the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Methods and Findings EAE was induced in mice by immunization with a myelin autoantigen. Intravenous application of TREM2-transduced bone marrow–derived myeloid precursor cells at the EAE peak led to an amelioration of clinical symptoms, reduction in axonal damage, and prevention of further demyelination. TREM2-transduced myeloid cells applied intravenously migrated into the inflammatory spinal cord lesions of EAE-diseased mice, showed increased lysosomal and phagocytic activity, cleared degenerated myelin, and created an anti-inflammatory cytokine milieu within the CNS. Conclusions Intravenously applied bone marrow–derived and TREM2-tranduced myeloid precursor cells limit tissue destruction and facilitate repair within the murine CNS by clearance of cellular debris during EAE. TREM2 is a new attractive target for promotion of repair and resolution of inflammation in multiple sclerosis and other neuroinflammatory diseases.

Takahashi, Kazuya; Prinz, Marco; Stagi, Massimiliano; Chechneva, Olga; Neumann, Harald

2007-01-01

10

Hematopoietic progenitor cell lines with myeloid and lymphoid potential.  

PubMed

Investigation of immune-cell differentiation and function is limited by shortcomings of suitable and scalable experimental systems. Here we show that retroviral delivery of an estrogen-regulated form of Hoxb8 into mouse bone marrow cells can be used along with Flt3 ligand to conditionally immortalize early hematopoietic progenitor cells (Hoxb8-FL cells). Hoxb8-FL cells have lost self-renewal capacity and potential to differentiate into megakaryocytes and erythrocytes but retain the potential to differentiate into myeloid and lymphoid cells. They differentiate in vitro and in vivo into macrophages, granulocytes, dendritic cells, B lymphocytes and T lymphocytes that are phenotypically and functionally indistinguishable from their primary counterparts. Quantitative in vitro assays indicate that myeloid and B-cell potential of Hoxb8-FL cells is comparable to that of primary lymphoid-primed multipotent progenitors, whereas T-cell potential is diminished. The simplicity of this system and the unlimited proliferative capacity of Hoxb8-FL cells will enable studies of immune-cell differentiation and function. PMID:23749299

Redecke, Vanessa; Wu, Ruiqiong; Zhou, Jingran; Finkelstein, David; Chaturvedi, Vandana; High, Anthony A; Häcker, Hans

2013-06-09

11

Myeloid skewing in murine autoimmune arthritis occurs in hematopoietic stem and primitive progenitor cells  

PubMed Central

Skewing toward myeloid cell production is often observed in chronic inflammation and autoimmune diseases. Herein, we determined whether persistent myeloid activation and proinflammatory output occurring in pathologic conditions is at the level of hematopoietic stem and primitive progenitor cells (HSPPCs). By using a mouse arthritis model, we found that even though HSPPCs in arthritis still retained the capacity to differentiate into different lineages, they acquired enhanced in vitro and in vivo propensity in a disease-dependent manner to generate myeloid cells, the key perpetrators of tissue damage in arthritis. This myeloid skewing was cell intrinsic, as arthritic HSPPCs up-regulate myeloid-specific transcripts including S100a8. Exogenous S100a8 promoted myeloid cell output from wild-type HSPPCs, suggesting mechanistic involvement of this gene in the myeloid priming that occurs in arthritic HSPPCs. Therefore, our results indicate that in arthritic mice, HSPPCs adopt a pathologic state that favors disease persistence.

Oduro, Kwadwo A.; Liu, Fang; Tan, Qing; Kim, Chan-Kyu; Lubman, Olga; Fremont, Daved; Mills, Jason C.

2012-01-01

12

Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function  

PubMed Central

Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b–/loLy6Chi BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4+ T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4+ and CD8+ T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell–suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint.

Charles, Julia F.; Hsu, Lih-Yun; Niemi, Erene C.; Weiss, Arthur; Aliprantis, Antonios O.; Nakamura, Mary C.

2012-01-01

13

Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age  

PubMed Central

In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.

Pang, Wendy W.; Price, Elizabeth A.; Sahoo, Debashis; Beerman, Isabel; Maloney, William J.; Rossi, Derrick J.; Schrier, Stanley L.; Weissman, Irving L.

2011-01-01

14

The histone acetyl transferase activity of monocytic leukemia zinc finger is critical for the proliferation of hematopoietic precursors  

PubMed Central

The monocytic leukemia zinc finger (MOZ) gene encodes a large multidomain protein that contains, besides other domains, 2 coactivation domains for the transcription factor Runx1/acute myeloid leukemia 1 and a histone acetyl transferase (HAT) catalytic domain. Recent studies have demonstrated the critical requirement for the complete MOZ protein in hematopoietic stem cell development and maintenance. However, the specific function of the HAT activity of MOZ remains unknown, as it has been shown that MOZ HAT activity is not required either for its role as Runx1 coactivator or for the leukemic transformation induced by MOZ transcriptional intermediary factor 2 (TIF2). To assess the specific requirement for this HAT activity during hematopoietic development, we have generated embryonic stem cells and mouse lines carrying a point mutation that renders the protein catalytically inactive. We report in this study that mice exclusively lacking the HAT activity of MOZ exhibit significant defects in the number of hematopoietic stem cells and hematopoietic committed precursors as well as a defect in B-cell development. Furthermore, we demonstrate that the failure to maintain a normal number of hematopoietic precursors is caused by the inability of HAT?/? cells to expand. These results indicate a specific role of MOZ-driven acetylation in controlling a desirable balance between proliferation and differentiation during hematopoiesis.

Perez-Campo, Flor M.; Borrow, Julian; Kouskoff, Valerie

2009-01-01

15

Hematopoietic precursor cells transiently reestablish permissiveness for X inactivation.  

PubMed

Xist is the trigger for X inactivation in female mammals. The long noncoding Xist RNA localizes along one of the two female X chromosomes and initiates chromosome-wide silencing in the early embryo. In differentiated cells, Xist becomes dispensable for the maintenance of the inactive X, and its function for initiation of silencing is lost. How Xist mediates gene repression remains an open question. Here, we use an inducible Xist allele in adult mice to identify cells in which Xist can cause chromosome-wide silencing. We show that Xist has the ability to initiate silencing in immature hematopoietic precursor cells. In contrast, hematopoietic stem cells and mature blood cells are unable to initiate ectopic X inactivation. This indicates that pathways critical for silencing are transiently activated in hematopoietic differentiation. Xist-responsive cell types in normal female mice show a change of chromatin marks on the inactive X. However, dosage compensation is maintained throughout hematopoiesis. Therefore, Xist can initiate silencing in precursors with concomitant maintenance of dosage compensation. This suggests that Xist function is restricted in development by the limited activity of epigenetic pathways rather than by a change in the responsiveness of chromatin between embryonic and differentiated cell types. PMID:16980619

Savarese, Fabio; Flahndorfer, Katja; Jaenisch, Rudolf; Busslinger, Meinrad; Wutz, Anton

2006-10-01

16

Myeloid-derived suppressor cells in allogeneic hematopoietic stem cell transplantation  

PubMed Central

Accumulating evidence suggests that myeloid-derived suppressor cells (MDSCs) underpin an immunological checkpoint that is activated during inflammation or “inflammatory-like” conditions like cancer. Here, we discuss the identification of MDSCs in patients receiving allogeneic hematopoietic stem cell transplantation and their potential as therapeutic targets or tools for improving the efficacy of this treatment.

Le Blanc, Katarina; Jitschin, Regina; Mougiakakos, Dimitrios

2013-01-01

17

Blood-Borne Seeding by Hematopoietic and Endothelial Precursors from the Allantois  

Microsoft Academic Search

Until now the allantois has not been considered as a hematopoietic organ. Here we report experimental evidence demonstrating the in situ emergence of both hematopoietic and endothelial precursors in the avian allantoic bud. When the prevascularized allantoic bud from a quail embryo was grafted in the coelom of a chicken host, hematopoietic and endothelial cells later were found in the

Arianna Caprioli; Thierry Jaffredo; Rodolphe Gautier; Cecile Dubourg; Francoise Dieterlen-Lievre

1998-01-01

18

Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates  

Microsoft Academic Search

Recent studies have shown that cells from the bone marrow can give rise to differentiated skeletal muscle fibers. However, the mechanisms and identities of the cell types involved have remained unknown, and the validity of the observation has been questioned. Here, we use transplantation of single CD45+ hematopoietic stem cells (HSCs) to demonstrate that the entire circulating myogenic activity in

Fernando D Camargo; Rahshaana Green; Yassemi Capetenaki; Kathyjo A Jackson; Margaret A Goodell

2003-01-01

19

Erythro-myeloid progenitors: "Definitive" hematopoiesis in the conceptus prior to the emergence of hematopoietic stem cells.  

PubMed

Erythro-myeloid progenitors (EMP) serve as a major source of hematopoiesis in the developing conceptus prior to the formation of a permanent blood system. In this review, we summarize the current knowledge regarding the emergence, fate, and potential of this hematopoietic stem cell (HSC)-independent wave of hematopoietic progenitors, focusing on the murine embryo as a model system. A better understanding of the temporal and spatial control of hematopoietic emergence in the embryo will ultimately improve our ability to derive hematopoietic stem and progenitor cells from embryonic stem cells and induced pluripotent stem cells to serve therapeutic purposes. PMID:24095199

Frame, Jenna M; McGrath, Kathleen E; Palis, James

2013-10-02

20

Agnogenic myeloid metaplasia: a clonal proliferation of hematopoietic stem cells with secondary myelofibrosis.  

PubMed

The glucose-6-phosphate dehydrogenase (G-6-PD) types and chromosomes of hematopoietic and other tissues were determined in a woman with agnogenic myeloid metaplasia. The patient was heterozygous at the X-linked G-6-PD locus so that both B and A isoenzymes were found in nonhematopoietic cells. In contrast, only one G-6-PD type was found in granulocytes, red cells, and platelets. She also had a distinctive chromosome abnormality in blood cells but not in other tissues. These results indicate that agnogenic myeloid metaplasia is a disorder of a pluripotent stem cell and provide strong evidence that it is of clonal origin. In contrast to blood cells, the patient's cultured marrow "fibroblasts" had normal chromosomes and both B and A G-6-PD types, suggesting that the marrow fibrosis is a secondary abnormality. Thus, at least in this case of agnogenic myeloid metaplasia, the hematopoietic cell proliferation appears to be clonal, and, by inference, possibly neoplastic, whereas the marrow fibrosis is probably not clonal, and therefore appears to be secondary. PMID:620081

Jacobson, R J; Salo, A; Fialkow, P J

1978-02-01

21

GATA-2 mediated regulation of normal hematopoietic stem/progenitor cell function, myelodysplasia and myeloid leukemia  

PubMed Central

Unremitting blood cell production throughout the lifetime of an organism is reliant on hematopoietic stem cells (HSCs). A rare and relatively quiescent cell type harbored in adult bone marrow, HSCs are, on entry into cell cycle fated to self-renew, undergo apoptosis or differentiate to progenitors (HPCs) that eventually yield specific classes of blood cells. Disruption of these HSC cell fate decisions is considered to be fundamental to the development of leukemia. Much effort has therefore been placed on understanding the molecular pathways that regulate HSC cell fate decisions and how these processes are undermined during leukemia. Transcription factors have emerged as critical regulators in this respect. Here we review the participation of zinc finger transcription factor GATA-2 in regulating normal hematopoietic stem and progenitor cell functionality, myelodysplasia and myeloid leukemia.

Rodrigues, Neil P.; Tipping, Alex J.; Wang, Zhengke; Enver, Tariq

2011-01-01

22

A hybrid form of myeloid/NK-cell acute leukemia and myeloid/NK-cell precursor acute leukemia.  

PubMed

Natural killer (NK)-cell leukemia/lymphoma is a rare entity that has been defined only in recent years. In the Revised European-American Lymphoma and World Health Organization classifications, only the mature NK-cell malignancies are included. However, at least 3 types of precursor NK-cell neoplasms have been reported in the literature. These include myeloid/NK-cell acute leukemia, myeloid/NK-cell precursor acute leukemia, and blastic NK-cell lymphoma/leukemia. These leukemias are characterized by the presence of blasts, which express CD56, in the peripheral blood, bone marrow, lymph nodes, and/or extranodal tissues. We report a case that is morphologically consistent with myeloid/NK-cell acute leukemia but immunologically is myeloid/NK-cell precursor acute leukemia. This case is unique in its cutaneous presentation without involvement of the peripheral blood. Extensive flow cytometric studies were performed on the skin biopsy and bone marrow aspirate specimens, which included many markers that had not been tested before in these entities. The clinical implications of these findings are discussed. PMID:12792926

Sun, Tsieh; Pashaei, Shayesteh; Jaffrey, Ira; Ryder, John

2003-05-01

23

Induction of Multipotential Hematopoietic Progenitors from Human Pluripotent Stem Cells via Respecification of Lineage-Restricted Precursors.  

PubMed

Human pluripotent stem cells (hPSCs) represent a promising source of patient-specific cells for disease modeling, drug screens, and cellular therapies. However, the inability to derive engraftable human hematopoietic stem and progenitor cells (HSPCs) has limited their characterization to in vitro assays. We report a strategy to respecify lineage-restricted CD34(+)CD45(+) myeloid precursors derived from hPSCs into multilineage progenitors that can be expanded in vitro and engrafted in vivo. HOXA9, ERG, and RORA conferred self-renewal and multilineage potential in vitro and maintained primitive CD34(+)CD38(-) cells. Screening cells via transplantation revealed that two additional factors, SOX4 and MYB, conferred engraftment. Progenitors specified with all five factors gave rise to reproducible short-term engraftment with myeloid and erythroid lineages. Erythroid precursors underwent hemoglobin switching in vivo, silencing embryonic and activating adult globin expression. Our combinatorial screening approach establishes a strategy for obtaining transcription-factor-mediated engraftment of blood progenitors from human pluripotent cells. PMID:24094326

Doulatov, Sergei; Vo, Linda T; Chou, Stephanie S; Kim, Peter G; Arora, Natasha; Li, Hu; Hadland, Brandon K; Bernstein, Irwin D; Collins, James J; Zon, Leonard I; Daley, George Q

2013-10-01

24

Challenges for Allogeneic Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors  

Microsoft Academic Search

Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (HSCT) scene in CML has changed dramatically. The number of patients receiving HSCT in first chronic phase (CP) has declined rapidly, as allogeneic HSCT in CP is now performed in these patients only in case

Anthony Oyekunle; Evgeny Klyuchnikov; Sunday Ocheni; Nicolaus Kröger; Axel R. Zander; Michele Baccarani; Ulrike Bacher

2011-01-01

25

Myeloid/natural killer cell precursor acute leukemia diagnosed by cell marker analysis.  

PubMed

We report a case of myeloid/natural killer cell precursor acute leukemia. A 68-year-old man was diagnosed as having lymphoma in his neck, and was referred to our department for further examination and treatment. After admission, blastoid-cells appeared and increased rapidly in his peripheral blood. Cell marker analysis revealed that the blastoid-cells expressed CD7, CD56, CD33, and CD34. He was then diagnosed with myeloid/natural killer cell precursor leukemia. This form of leukemia was recently established as a distinct disease entity. Further clinicopathological evaluation and the establishment of treatment are necessary. PMID:23823098

Miura, Rika; Yoshimi, Mayumi; Kikuchi, Yuji; Takahashi, Tsuyoshi

2013-06-01

26

Computational Modeling of the Hematopoietic Erythroid-Myeloid Switch Reveals Insights into Cooperativity, Priming, and Irreversibility  

PubMed Central

Hematopoietic stem cell lineage choices are decided by genetic networks that are turned ON/OFF in a switch-like manner. However, prior to lineage commitment, genes are primed at low expression levels. Understanding the underlying molecular circuitry in terms of how it governs both a primed state and, at the other extreme, a committed state is of relevance not only to hematopoiesis but also to developmental systems in general. We develop a computational model for the hematopoietic erythroid-myeloid lineage decision, which is determined by a genetic switch involving the genes PU.1 and GATA-1. Dynamical models based upon known interactions between these master genes, such as mutual antagonism and autoregulation, fail to make the system bistable, a desired feature for robust lineage determination. We therefore suggest a new mechanism involving a cofactor that is regulated as well as recruited by one of the master genes to bind to the antagonistic partner that is necessary for bistability and hence switch-like behavior. An interesting fallout from this architecture is that suppression of the cofactor through external means can lead to a loss of cooperativity, and hence to a primed state for PU.1 and GATA-1. The PU.1–GATA-1 switch also interacts with another mutually antagonistic pair, C/EBP?–FOG-1. The latter pair inherits the state of its upstream master genes and further reinforces the decision due to several feedback loops, thereby leading to irreversible commitment. The genetic switch, which handles the erythroid-myeloid lineage decision, is an example of a network that implements both a primed and a committed state by regulating cooperativity through recruitment of cofactors. Perturbing the feedback between the master regulators and downstream targets suggests potential reprogramming strategies. The approach points to a framework for lineage commitment studies in general and could aid the search for lineage-determining genes.

Chickarmane, Vijay; Enver, Tariq; Peterson, Carsten

2009-01-01

27

HoxB4 Confers Definitive Lymphoid-Myeloid Engraftment Potential on Embryonic Stem Cell and Yolk Sac Hematopoietic Progenitors  

Microsoft Academic Search

The extent to which primitive embryonic blood progenitors contribute to definitive lymphoid-myeloid hematopoiesis in the adult remains uncertain. In an effort to characterize factors that distinguish the definitive adult hematopoietic stem cell (HSC) and primitive progenitors derived from yolk sac or embryonic stem (ES) cells, we examined the effect of ectopic expression of HoxB4, a homeotic selector gene implicated in

Michael Kyba; Rita C. R. Perlingeiro; George Q. Daley

2002-01-01

28

EVI1 and MDS1/EVI1 Expression During Primary Human Hematopoietic Progenitor Cell Differentiation into Various Myeloid Lineages  

PubMed Central

Background and Aim Overexpression of ecotropic viral integration site 1 (EVI1) is associated with aggressive disease in myeloid leukemia. We therefore studied its expression and function in cluster of differentiation 34 positive (CD 34+) primary human hematopoietic progenitor cells. Materials and Methods CD34+ cells were differentiated into various myeloid lineages using appropriate cytokines. EVI1 expression was measured by quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) and intranuclear fluorescence activated cell sorting (FACS). Experimental manipulation of EVI1 levels was achieved using retroviral infection. Results EVI1 mRNA and its variant myelodysplastic syndrome 1 (MDS1)/EVI1, which gives rise to a partially antagonistic protein, were detectable in CD34+ cells, but their levels declined rapidly during differentiation into the granulocytic, monocytic, dendritic, erythroid, and megakaryocytic lineages. Similarly, EVI1 protein levels decreased during myeloid differentiation. Attempts to experimentally express EVI1 in CD34+ and U937 cells indicated that ectopic expression of EVI1 may cause growth arrest, apoptosis and/or senescence of human hematopoietic cells. Conclusion EVI1 is expressed in human hematopoietic progenitor cells, but is down-regulated during differentiation. Ectopic expression of EVI1 may activate cellular safeguards against oncogene activation.

Steinleitner, Katarina; Rampetsreiter, Paulina; Koffel, Rene; Ramanathan, Gajalakshmi; Mannhalter, Christine; Strobl, Herbert; Wieser, Rotraud

2012-01-01

29

Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease.  

PubMed

Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.Molecular Therapy (2013); 21 10, 1938-1949. doi:10.1038/mt.2013.141. PMID:23748415

Sergijenko, Ana; Langford-Smith, Alexander; Liao, Ai Y; Pickford, Claire E; McDermott, John; Nowinski, Gabriel; Langford-Smith, Kia J; Merry, Catherine Lr; Jones, Simon A; Wraith, J Edmond; Wynn, Robert F; Wilkinson, Fiona L; Bigger, Brian W

2013-06-07

30

Isolated central nervous system relapse of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation  

PubMed Central

Background This case report highlights the relevance of quantifying the BCR-ABL gene in cerebrospinal fluid of patients with suspected relapse of chronic myeloid leukemia in the central nervous system. Case presentation We report on a female patient with isolated central nervous system relapse of chronic myeloid leukemia (CML) during peripheral remission after allogeneic hematopoietic stem cell transplantation. The patient showed a progressive cognitive decline as the main symptom. MRI revealed a hydrocephalus and an increase in cell count in the cerebrospinal fluid (CSF) with around 50% immature blasts in the differential count. A highly elevated BCR-ABL/ ABL ratio was detected in the CSF, whilst the ratio for peripheral blood and bone marrow was not altered. On treatment of the malresorptive hydrocephalus with shunt surgery, the patient showed an initial cognitive improvement, followed by a secondary deterioration. At this time, the cranial MRI showed leukemic infiltration of lateral ventricles walls. Hence, intrathecal administration of cytarabine, methotrexate, and dexamethasone was initiated, which caused a significant decrease of cells in the CSF. Soon after, the patient demonstrated significant cognitive improvement with a good participation in daily activities. At a later time point, after the patient had lost the major molecular response of CML, therapy with dasatinib was initiated. In a further follow-up, the patient was neurologically and hematologically stable. Conclusions In patients with treated CML, the rare case of an isolated CNS blast crisis has to be taken into account if neurological symptoms evolve. The analysis of BCR-ABL in the CSF is a further option for the reliable detection of primary isolated relapse of CML in these patients.

2012-01-01

31

Myeloid/Microglial Driven Autologous Hematopoietic Stem Cell Gene Therapy Corrects a Neuronopathic Lysosomal Disease  

PubMed Central

Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.

Sergijenko, Ana; Langford-Smith, Alexander; Liao, Ai Y; Pickford, Claire E; McDermott, John; Nowinski, Gabriel; Langford-Smith, Kia J; Merry, Catherine LR; Jones, Simon A; Wraith, J Edmond; Wynn, Robert F; Wilkinson, Fiona L; Bigger, Brian W

2013-01-01

32

PRIMITIVE ADULT HEMATOPOIETIC STEM CELLS CAN FUNCTION AS OSTEOBLAST PRECURSORS  

Technology Transfer Automated Retrieval System (TEKTRAN)

Osteoblasts are continually recruited from stem cell pools to maintain bone. Although their immediate precursor is a plastic-adherent mesenchymal stem cell able to generate tissues other than bone, increasing evidence suggests the existence of a more primitive cell that can differentiate to both hem...

33

Clonal analysis reveals a common progenitor for endothelial, myeloid, and lymphoid precursors in umbilical cord blood  

PubMed Central

Rationale Several studies demonstrate that hematopoietic tissues are a source of endothelial progenitor cells (EPCs), which contribute to newly formed blood vessels during tissue repair in adults. However, it is not clear which cell type in these hematopoietic tissues gives rise to EPCs. Objective To identity the origin of endothelial progenitors within the hematopoietic hierarchy, and assess their in vivo revascularization potential. Methods and Results Using a single cell sorting approach and in vitro multi-lineage differentiation assays, here we show that individual CD34+CD45+CD133+CD38+ cells from cord blood uniquely have the ability to differentiate into T and B lymphoid, myeloid, and endothelial cells. The latter were characterized by the expression of VE-cadherin, KDR, vWF, eNOs, the lack of CD45, CD133 and c-fms. Unexpectedly when transplanted into hind-limb ischemic NOD-scid IL2Rgammanull mice, freshly-isolated CD34+CD45+CD133+CD38+ cells maintained their hematopoietic identity and were rarely found to integrate into host blood vessels. Nevertheless, they significantly improve perfusion, most likely through a paracrine mechanism. On the other hand, endothelial cells derived in vitro from this fraction, are able to form vessels in vivo in both Matrigel plug and hind-limb ischemia transplantation assays. Conclusions These findings indicate that the CD34+CD45+CD133+CD38+ cell fraction contains a common progenitor for the hematopoietic and vascular lineages, and may represent a valuable cell source for therapeutic applications.

Ramos, Aline Lisie; Darabi, Radbod; Akbarloo, Nasrin; Borges, Luciene; Catanese, Jacquelyn; Dineen, Sean P.; Brekken, Rolf A.; Perlingeiro, Rita C. R.

2010-01-01

34

Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia  

PubMed Central

Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM+) and 900 subjects who did not receive IM before HCT (IM?) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM+ and IM? groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.

Kukreja, Manisha; Wang, Tao; Giralt, Sergio A.; Szer, Jeffrey; Arora, Mukta; Woolfrey, Ann E.; Cervantes, Francisco; Champlin, Richard E.; Gale, Robert Peter; Halter, Joerg; Keating, Armand; Marks, David I.; McCarthy, Philip L.; Olavarria, Eduardo; Stadtmauer, Edward A.; Abecasis, Manuel; Gupta, Vikas; Khoury, H. Jean; George, Biju; Hale, Gregory A.; Liesveld, Jane L.; Rizzieri, David A.; Antin, Joseph H.; Bolwell, Brian J.; Carabasi, Matthew H.; Copelan, Edward; Ilhan, Osman; Litzow, Mark R.; Schouten, Harold C.; Zander, Axel R.; Horowitz, Mary M.; Maziarz, Richard T.

2008-01-01

35

Growth after hematopoietic stem cell transplantation in children with acute myeloid leukemia.  

PubMed

Previous studies have shown that hematopoietic stem cell transplantation (HSCT) may result in growth impairment. The purpose of this study was to evaluate the growth during 5 yr after HSCT and to determine factors that influence final adult height (FAH). We retrospectively reviewed the medical records of acute myeloid leukemia (AML) patients who received HSCT. Among a total of 37 eligible patients, we selected 24 patients who began puberty at 5 yr after HSCT (Group 1) and 19 patients who reached FAH without relapse (Group 2). In Group 1, with younger age at HSCT, sex, steroid treatment, hypogonadism and hypothyroidism were not significantly associated with growth impairment 5 yr after HSCT. History of radiotherapy (RT) significantly impaired the 5 yr growth after HSCT. Chronic graft-versus-host disease (cGVHD) only temporarily impaired growth after HSCT. In Group 2, with younger age at HSCT, steroid treatment and hypogonadism did not significantly reduce FAH. History of RT significantly reduced FAH. Growth impairment after HSCT may occur in AML patients, but in patients without a history of RT, growth impairment seemed to be temporary and was mitigated by catch-up growth. PMID:23341720

Chung, Seung Joon; Park, Seung Wan; Kim, Min Kyoung; Kang, Min Jae; Lee, Young Ah; Lee, Seong Yong; Shin, Choong Ho; Yang, Sei Won; Kang, Hyoung Jin; Park, Kyung Duk; Shin, Hee Young; Ahn, Hyo Seop

2013-01-08

36

Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns.  

PubMed

Progress in the last decade has improved the understanding of leukemia biology. Molecular markers in combinations with cytogenetics have improved the risk stratification of acute myeloid leukemia (AML) and informed decision-making. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allogeneic hematopoietic cell transplantation (HCT) for a larger number of patients. In this review, the positioning of HCT in the management of patients with AML is evaluated in view of changing risk/benefit ratios associated with both conventional treatments and transplantation, and some of the controversies are addressed in light of emerging data. Increasing data demonstrate outcomes of alternative donor transplantation approaching HLA-identical sibling donors in high-risk AML supporting the inclusion of alternative donors in trials of prospective studies evaluating post remission strategies for high-risk AML. The use of reduced-intensity conditioning has expanded the eligibility of HCT to older patients with AML, and outcome data are encouraging. Continued study of HCT versus alternative therapies is required to optimize patients' outcomes in AML. PMID:21098397

Gupta, Vikas; Tallman, Martin S; Weisdorf, Daniel J

2010-11-22

37

Hematopoietic stem cell transplantation for acute myeloid leukemia: to whom, when, and how.  

PubMed

Allogeneic hematopoietic stem cell transplant (HSCT) is an established treatment modality with curative potential for acute myeloid leukemia (AML). There has been a significant rise in the number of HSCT procedures performed over the past decade due in part to improved supportive care and innovative techniques such as reduced-intensity conditioning. Expanding alternative donor options such as umbilical cord blood and haploidentical HSCT, taken together with improved outcomes of matched unrelated donors, has resulted in a suitable donor for most patients with an HSCT indication. Recent advances in molecular diagnostics that incorporate genetic mutational analysis into existing cytogenetic-based models should improve selection of patients at high risk of relapse most likely to benefit from HSCT. Improvements in minimal residual disease monitoring hold promise for adding prognostic information, and informing the clinician of impending relapse. The choice of the conditioning regimen involves weighing a patient's unique toxicity and relapse risks. Despite improvements, relapse remains the primary source of treatment failure after HSCT for treatment of AML. The introduction of novel therapies into the clinic, together with improved patient selection, offers hope for decreasing relapse and improving outcomes for AML patients. PMID:23959811

Magenau, John; Couriel, Daniel R

2013-10-01

38

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia when a matched related donor is not available.  

PubMed

Although for many patients with acute myeloid leukemia (AML) allogeneic hematopoietic cell transplantation (HCT) from a matched related donor provides the best, and sometimes the sole chance for cure, only about 30% of individuals have HLA-matched family members. Fortunately, recent advances on a number of fronts have expanded the acceptable donor pool. With the use of high-resolution typing, HCT outcomes using unrelated donors matched at HLA-A, -B, -C and -DRB1 give results very similar to those expected with matched related donors. A single mismatch, as determined either by low- or high-resolution testing, results in modestly worse outcomes, with mismatches at B or C better tolerated than mismatches at A or DRB1. Initial results of umbilical cord blood transplantation for adults showed a clear association of cell dose and outcome, limiting the procedure to a minority of adults where cord bloods with at least 2.5 or 3x10(7) total nucleated cells/kg could be found. More recently, the use of double cord transplants has shown considerable promise, lowering the risk of graft rejection and possibly the risk of relapse as well. Haploidentical transplantation using T-cell-replete marrow and post-transplant high-dose cyclophosphamide, or T-cell-depleted peripheral blood and marrow containing high doses of CD34+ cells is under investigation. Together, these various approaches are broadening the transplant options for patients with AML. PMID:19074118

Appelbaum, Frederick R

2008-01-01

39

CpG oligodeoxynucleotide induces bone marrow precursor cells into myeloid-derived suppressor cells.  

PubMed

Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) perform a number of functions in different immunological settings. In standard in vitro experiments, DCs are produced from mouse bone marrow (BM) cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Our previous study demonstrated that BM precursor cells could differentiate into MDSCs when co-cultured with poly (I:C). In the present study, BM precursor cells cultured in GM-CSF and IL-4 were treated with CpG oligodeoxynucleotide (CpG ODN). We observed that Gr1+CD11b+ cells exhibiting MDSC functions accumulated in the co-culture system. A similar phenomenon was also observed in Listeria monocytogenes-infected mice. In conclusion, we demonstrated that prolonged CpG ODN stimulation could inhibit the development of DCs and induce the differentiation of BM precursor cells into MDSCs. PMID:23982226

Chen, Jie; Deng, Chengyu; Shi, Qingmin; Jiang, Jun; Zhang, Yongbo; Shan, Wei; Sun, Weimin

2013-08-27

40

Development of Mature and Functional Human Myeloid Subsets in Hematopoietic Stem Cell-Engrafted NOD\\/SCID\\/IL2r?KO Mice  

Microsoft Academic Search

Although physiological development of human lymphoid subsets has become well documented in humanized mice, in vivo development of human myeloid subsets in a xenotransplantation setting has remained unevaluated. Therefore, we investigated in vivo differentiation and function of human myeloid subsets in NOD\\/SCID\\/IL2r?(null) (NSG) mouse recipients transplanted with purified lineage(-)CD34(+)CD38(-) cord blood hematopoietic stem cells. At 4-6 mo posttransplantation, we identified

Satoshi Tanaka; Yoriko Saito; Jun Kunisawa; Yosuke Kurashima; Taichi Wake; Nahoko Suzuki; Leonard D Shultz; Hiroshi Kiyono; Fumihiko Ishikawa

2012-01-01

41

Myeloid\\/natural killer cell precursor acute leukemia with multiple subcutaneous nodules as the initial presentation: a case report and literature review  

Microsoft Academic Search

Myeloid\\/natural killer (NK) cell precursor acute leukemia is a rare neoplasm, which is characterized by high incidence of\\u000a extramedullary infiltration, especially in the mediastinum and lymph nodes, an aggressive course and poor prognosis. As coexpressing\\u000a myeloid and NK-cell antigens, myeloid\\/NK-cell precursor acute leukemia (MNKL) may pose diagnostic difficulty. Because the\\u000a developmental pathway of normal NK cells is not well understood,

Yan Ma; Bobin Chen; Xiaoping Xu; Guowei Lin

2009-01-01

42

Identification of key genes responsible for cytokine-induced erythroid and myeloid differentiation and switching of hematopoietic stem cells by RAGE  

Microsoft Academic Search

We utilized a unique culture system to analyze the expression patterns of gene, protein, and cell surface antigen, and the biological process of the related genes in erythroid and myeloid differentiation and switching of hematopoietic stem cells (HSCs) in response to cytokine alterations. Gene-specific fragments (266) identified from five populations of cytokine-stimulated HSCs were categorized into three groups: (1) expressed

Ling Chen; Hong Zhang; Ying Shi; Kyung L Chin; Delia C Tang; Griffin P Rodgers

2006-01-01

43

An “Age” Structured Model of Hematopoietic Stem Cell Organization with Application to Chronic Myeloid Leukemia  

Microsoft Academic Search

Previously, we have modeled hematopoietic stem cell organization by a stochastic, single cell-based approach. Applications\\u000a to different experimental systems demonstrated that this model consistently explains a broad variety of in vivo and in vitro data. A major advantage of the agent-based model (ABM) is the representation of heterogeneity within the hematopoietic stem\\u000a cell population. However, this advantage comes at the price

Ingo Roeder; Maria Herberg; Matthias Horn

2009-01-01

44

Stem cell biology is population biology: differentiation of hematopoietic multipotent progenitors to common lymphoid and myeloid progenitors.  

PubMed

The hematopoietic stem cell (HSC) system is a demand control system, with the demand coming from the organism, since the products of the common myeloid and lymphoid progenitor (CMP, CLP respectively) cells are essential for activity and defense against disease. We show how ideas from population biology (combining population dynamics and evolutionary considerations) can illuminate the feedback control of the HSC system by the fully differentiated products, which has recently been verified experimentally. We develop models for the penultimate differentiation of HSC Multipotent Progenitors (MPPs) into CLP and CMP and introduce two concepts from population biology into stem cell biology. The first concept is the Multipotent Progenitor Commitment Response (MPCR) which is the probability that a multipotent progenitor cell follows a CLP route rather than a CMP route. The second concept is the link between the MPCR and a measure of Darwinian fitness associated with organismal performance and the levels of differentiated lymphoid and myeloid cells. We show that many MPCRs are consistent with homeostasis, but that they will lead to different dynamics of cells and signals following a wound or injury and thus have different consequences for Darwinian fitness. We show how coupling considerations of life history to dynamics of the HSC system and its products allows one to compute the selective pressures on cellular processes. We discuss ways that this framework can be used and extended. PMID:23327512

Mangel, Marc; Bonsall, Michael B

2013-01-17

45

Aging increases nuclear chromatin entropy of erythroid precursor cells in mice spleen hematopoietic tissue.  

PubMed

Despite recent advances in hematopoietic tissue research, effects of aging on hematopoietic erythroid precursor (EP) cells are unclear. In this article we present results suggesting that chromatin textural entropy of EP cells in mouse spleen increases with age, while chromatin homogeneity decreases. The experiment was conducted on a total of 32 male Swiss white mice. Spleen tissue was acquired from four age groups: 10 days, 1 month, 4 months, and 7 months old mice. A total of 640 randomly selected, nonoverlapping EP cell nuclei (20 per animal) were analyzed using the gray level co-occurrence matrix method. There was statistically highly significant difference between the age groups, both in chromatin entropy (ANOVA, F = 12.99, p < 0.0001) and in homogeneity (ANOVA, F = 7.05, p < 0.001). When the individual groups were compared (ANOVA post hoc test), statistical difference was detected in all group pairs, except between the animals 4 months and 7 months old, either in chromatin entropy or homogeneity. The detected increase of chromatin disorder in mouse juvenile period/early adulthood suggests that cell intrinsic factors such as epigenetic dysregulation and DNA damage accumulation may have an important role in EP cell aging. PMID:23058597

Pantic, Igor; Pantic, Senka; Paunovic, Jovana

2012-10-12

46

PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts  

PubMed Central

Missense mutations that reduce or abrogate myeloid cell expression of the F-BAR domain protein, proline serine threonine phosphatase-interacting protein 2 (PSTPIP2), lead to autoinflammatory disease involving extramedullary hematopoiesis, skin and bone lesions. However, little is known about how PSTPIP2 regulates osteoclast development. Here we examined how PSTPIP2 deficiency causes osteopenia and bone lesions, using the mouse PSTPIP2 mutations, cmo, which fails to express PSTPIP2 and Lupo, in which PSTPIP2 is dysfunctional. In both models, serum levels of the pro-osteoclastogenic factor, MIP-1?, were elevated and CSF-1 receptor (CSF-1R)–dependent production of MIP-1? by macrophages was increased. Treatment of cmo mice with a dual specificity CSF-1R and c-Kit inhibitor, PLX3397, decreased circulating MIP-1? and ameliorated the extramedullary hematopoiesis, inflammation, and osteopenia, demonstrating that aberrant myelopoiesis drives disease. Purified osteoclast precursors from PSTPIP2-deficient mice exhibit increased osteoclastogenesis in vitro and were used to probe the structural requirements for PSTPIP2 suppression of osteoclast development. PSTPIP2 tyrosine phosphorylation and a functional F-BAR domain were essential for PSTPIP2 inhibition of TRAP expression and osteoclast precursor fusion, whereas interaction with PEST-type phosphatases was only required for suppression of TRAP expression. Thus, PSTPIP2 acts as a negative feedback regulator of CSF-1R signaling to suppress inflammation and osteoclastogenesis.

Nacu, Viorel; Charles, Julia F.; Henne, William M.; McMahon, Harvey T.; Nandi, Sayan; Ketchum, Halley; Harris, Renee; Nakamura, Mary C.

2012-01-01

47

Daunorubicin, Cytarabine, and Cladribine Regimen Plus Radiotherapy and Donor Lymphocyte Infusion for Extramedullary Relapse of Acute Myeloid Leukemia after Hematopoietic Stem Cell Transplantation  

PubMed Central

Myeloid sarcoma is a rare tumor consisting of myeloid blasts that involve anatomic sites outside the bone marrow. Fatal prognosis is inevitable in patients with extramedullary relapse after hematopoietic stem cell transplantation (HSCT), and no standard treatments are available yet. We report the first case of extramedullary relapse after HSCT treated with a combination of daunorubicin, cytarabine, and cladribine (DAC) regimen plus radiotherapy and donor lymphocyte infusion (DLI). This treatment induced a new and durable remission in our patient. The favorable toxicity profile and the reduced cost make this combination worthy of further investigations.

Sanna, Marco; Caocci, Giovanni; Vacca, Adriana; Piras, Eugenia; Orru, Federica; La Nasa, Giorgio

2013-01-01

48

The use of isobaric tag peptide labeling (iTRAQ) and mass spectrometry to examine rare, primitive hematopoietic cells from patients with chronic myeloid leukemia  

Microsoft Academic Search

Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell disease, associated with a t(9, 22) chromosomal translocation\\u000a leading to formation of the BCR\\/ABL chimeric protein, which has an intrinsic tyrosine kinase activity. Recently, the BCR\\/ABL\\u000a tyrosine kinase inhibitor imatinib mesylate (imatinib) has been successfully used clinically, although, disease relapse can\\u000a still occur. The precise detail of the mechanism by which

Stephen D. Griffiths; John Burthem; Richard D. Unwin; Tessa L. Holyoake; Junia V. Melo; Guy S. Lucas; Anthony D. Whetton

2007-01-01

49

Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia  

Microsoft Academic Search

There is substantial need to improve the outcome of patients with high-risk acute myeloid leukemia (AML). The clinical trial reported here investigated a new approach of up-front allogeneic hematopoietic stem cell transplantation (HSCT), provided a median of 40 days (range 22–74) after diagnosis, in twenty-six consecutive patients with newly-diagnosed high-risk AML characterized by poor-risk cytogenetics (n=19) or inadequate blast clearance

U Platzbecker; C Thiede; M Füssel; G Geissler; T Illmer; B Mohr; M Hänel; R Mahlberg; U Krümpelmann; F Weissinger; M Schaich; C Theuser; G Ehninger; M Bornhäuser

2006-01-01

50

Factors influencing hematopoietic recovery after autologous blood stem cell transplantation in patients with acute myeloblastic leukemia and with non-myeloid malignancies  

Microsoft Academic Search

Factors influencing hematopoietic recovery (HR) after autologous blood stem cell transplantation (ABSCT) were analyzed in 73 patients with various non-myeloid malignancies (NMM), and in 58 patients with acute myeloblastic leukemia (AML). Peripheral blood stem cells were collected following mobilization with chemotherapy, granulocyte colony-stimulating factor (G-CSF), or chemotherapy plus G-CSF. The conditioning regimen used consisted of either chemotherapy alone (112 cases)

A Carral; J de la Rubia; G Martín; J Martínez; G Sanz; I Jarque; A Sempere; MA Soler; ML Marty; MA Sanz

2002-01-01

51

Survival after cord blood transplantation from unrelated donor as a second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia  

Microsoft Academic Search

The Japan Cord Blood Bank Network (JCBBN) reports the treatment of 22 children with acute myeloid leukemia (AML) who received\\u000a umbilical cord blood transplantation from unrelated donors (CBT) as their second hematopoietic stem cell transplantation (HSCT).\\u000a Provided by the JCBBN, between February 1997 and September 2006, 22 patients had CBT as a second HSCT. In the initial HSCT,\\u000a eight received

M. Oda; K. Isoyama; E. Ito; M. Inoue; M. Tsuchida; H. Kigasawa; K. Kato; S. Kato

2009-01-01

52

Overexpression of amyloid precursor protein in acute myeloid leukemia enhances extramedullary infiltration by MMP-2.  

PubMed

It is known that leukemia patients with extramedullary infiltration (EMI) have a worse prognosis than patients without it. Recent data indicate that the amyloid precursor protein (APP) is involved in cell adhesion, motility, and proliferation. The expression of APP and its prognostic significance in acute myeloid leukemia (AML) have not been studied. Our study shows that AML/ETO(+) leukemia patients that overexpress APP easily get EMI and that their long-term survival rate is lower than patients without overexpression of APP. In an in vitro study, we knocked down APP in Kasumi-1 cells using small interfering RNA (siRNA). Transwell data show that siRNA/APP substantially impairs cell migration, but it does not inhibit cell proliferation. Furthermore, by quantitative real-time polymerase chain reaction and Western blot, we found that siRNA/APP decreases MMP-2 expression in vitro. Our study provides a novel clue that APP is involved in the extramedullary infiltration of leukemia by MMP-2. PMID:23179400

Jiang, Ling; Yu, Guopan; Meng, Wei; Wang, Zhixiang; Meng, Fanyi; Ma, Wenli

2012-11-23

53

Hematopoietic Stem Cell Theory in Relation to Possible Lymphoblastic Conversion of Chronic Myeloid Leukemia  

Microsoft Academic Search

(CML) must be considered a clonal disease of a pluripotent hemato- poietic stem cell compartment. The Philadelphia chromosome (Ph' ) abnormal- ity (translocation of a portion of the lOng arms of chromosome 22 onto chromosome 91) is found not only in neutrohil precursors, but in precursors of red cells, eosinophils, and probably platelets2 as well as monocytes.3 These observations plus

Dane R. Boggs

1974-01-01

54

Busulfan and melphalan as conditioning regimen for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission  

PubMed Central

Background Allogeneic hematopoietic stem cell transplantation with HLA-identical donors has been established for the treatment of acute myeloid leukemia patients for over 30 years with a cure rate of 50% to 60%. Objectives To analyze the overall survival of patients and identify factors that influence the outcomes of this type of transplant in patients in 1st complete remission who received a busulfan and melphalan combination as conditioning regimen. Methods Twenty-five consecutive patients with acute myeloid leukemia were enrolled between 2003 and 2008. The median age was 34 years old (Range: 16 - 57 years). All patients received cyclosporine and methotrexate for prophylaxis against graft-versus-host disease. Median neutrophil engraftment time was 16 days (Range: 7 - 22 days) and 17 days (Range: 7 - 46 days) for platelets. Sinusoidal obstructive syndrome was observed in three patients, seven had grade II acute graft-versus-host disease and one extensive chronic graft-versus-host disease. Results The overall survival by the Kaplan-Meier method was 48% after 36 months with a plateau at 36 months after transplantation. Intensive consolidation with high-dose arabinoside resulted in an improved survival (p-value = 0.0001), as did grade II acute graft-versus-host disease (p-value = 0.0377) and mild chronic graft-versus-host disease (p-value < 0.0001). Thirteen patients died, five due to infection within 100 days of transplant, two due to hemorrhages, one to infection and graftversus-host disease and three relapses followed by renal failure (one) and infection (two). The cause of death could not be determined for two patients. Conclusion The busulfan and melphalan conditioning regimen is as good as other conditioning regimens providing an excellent survival rate.

Bueno, Nadjanara Dorna; Dulley, Frederico Luiz; Saboya, Rosaura; Amigo Filho, Jose Ulysses; Coracin, Fabio Luiz; Chamone, Dalton de Alencar Fischer

2011-01-01

55

Toll-like receptor 4/stem cell antigen 1 signaling promotes hematopoietic precursor cell commitment to granulocyte development during the granulopoietic response to Escherichia coli bacteremia.  

PubMed

In response to severe bacterial infection, bone marrow hematopoietic activity shifts toward promoting granulopoiesis. The underlying cell signaling mechanisms remain obscure. To study the role of Toll-like receptor 4 (TLR4)/stem cell antigen-1 (Sca-1) signaling in this process, bacteremia was induced in mice by intravenous injection of Escherichia coli. A subgroup of animals also received intravenous 5-bromo-2-deoxyuridine (BrdU). In a separate set of experiments, bone marrow lineage-negative (lin(-)) stem cell growth factor receptor-positive (c-kit(+)) Sca-1(-) cells containing primarily common myeloid progenitors were cultured in vitro without or with E. coli lipopolysaccharide (LPS). In genotypic background control mice, bacteremia significantly upregulated Sca-1 expression by lin(-) c-kit(+) cells, as reflected by a marked increase in BrdU-negative lin(-) c-kit(+) Sca-1(+) cells in the bone marrow. In mice with the TLR4 gene deletion, this bacteremia-evoked Sca-1 response was blocked. In vitro, LPS induced a dose-dependent increase in Sca-1 expression by cultured marrow lin(-) c-kit(+) Sca-1(-) cells. LPS-induced upregulation of Sca-1 expression was regulated at the transcriptional level. Inhibition of c-Jun N-terminal kinase/stress-activated protein kinase (JNK) activity with the specific inhibitor SP600125 suppressed LPS-induced upregulation of Sca-1 expression by marrow lin(-) c-kit(+) Sca-1(-) cells. Engagement of Sca-1 with anti-Sca-1 antibodies enhanced the expression of Sfpi1 spleen focus-forming virus (SFFV) proviral integration 1 (PU.1) in marrow lin(-) c-kit(+) Sca-1(-) cells cultured with LPS. Sca-1 null mice failed to maintain the marrow pool of granulopoietic cells following bacteremia. These results demonstrate that TLR4/Sca-1 signaling plays an important role in the regulation of hematopoietic precursor cell programming and their enhancement of granulocyte lineage commitment in response to E. coli bacteremia. PMID:23545304

Shi, Xin; Siggins, Robert W; Stanford, William L; Melvan, John N; Basson, Marc D; Zhang, Ping

2013-04-01

56

Challenges for allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia in the era of tyrosine kinase inhibitors.  

PubMed

Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (HSCT) scene in CML has changed dramatically. The number of patients receiving HSCT in first chronic phase (CP) has declined rapidly, as allogeneic HSCT in CP is now performed in these patients only in case of failure or intolerance of TKIs. Second, those CML patients who undergo allogeneic HSCT represent a selection of high-risk patients due to more advanced disease with high rates of accelerated or blast phase (being associated with an increased relapse risk), advanced age and relevant co-morbidities. Efforts at meeting these special challenges are being developed: treatment with TKIs aims to improve the pre-transplant remission status before HSCT. Dose-reduced conditioning protocols were introduced to decrease transplant-related mortality in patients with co-morbidities or older age. In the post-transplant period, TKIs may be administered for prophylaxis and for treatment of post-transplant relapse. Still, the outcome of patients in advanced CML phases remains guarded, and requires an improvement in current transplant strategies. PMID:21411987

Oyekunle, Anthony; Klyuchnikov, Evgeny; Ocheni, Sunday; Kröger, Nicolaus; Zander, Axel R; Baccarani, Michele; Bacher, Ulrike

2011-03-17

57

Acute Alcohol Intoxication Impairs the Hematopoietic Precursor Cell Response to Pneumococcal Pneumonia  

PubMed Central

Background Alcohol abuse is associated with an increased incidence and severity of pneumonia. In both the general population and in individuals consuming excess alcohol, Streptococcus pneumoniae is the most frequent lung infection pathogen. Alcoholic patients with pneumonia frequently present with granulocytopenia, which is predictive of increased mortality. The mechanisms underlying this impaired granulopoietic response to pneumococcal pneumonia have yet to be elucidated. Methods Acute alcohol intoxication was induced in mice 30 minutes before intrapulmonary infection with Streptococcus pneumoniae. Bone marrow and blood samples were collected. Bone marrow cells were also isolated from naïve mice and treated in vitro with plasma from mice infected with S.pneumoniae. Results Alcohol intoxication impaired the pneumococcal-induced increase in granulocyte recruitment into the alveolar space, decreased bacterial clearance from the lung, and increased mortality. Pneumococcal pneumonia significantly increased bone marrow lineage?c-Kit+Sca-1+ (LKS) cell number and colony forming unit – granulocytes and monocyte (CFU-GM) activity of these cells. Both enhanced proliferation of LKS cells and re-expression of Sca-1 surface protein on downstream progenitor cells bearing lineage?c-Kit+Sca-1? surface markers accounted for the expansion of marrow LSK cells during pneumonia. Alcohol intoxication impaired these two mechanisms of LKS cell population expansion and was associated with a relative granulocytopenia during pneumococcal lung infection. Conclusions Alcohol inhibits the hematopoietic precursor cell response to pneumonia which may serve as a mechanism underlying the granulocytopenia and impaired host defense in alcohol abusers with bacterial pneumonia.

Raasch, Caroline E.; Zhang, Ping; Siggins, Robert W.; LaMotte, Lynn R.; Nelson, Steve; Bagby, Gregory J.

2013-01-01

58

Genotypic and functional diversity of phenotypically defined primitive hematopoietic cells in patients with chronic myeloid leukemia.  

PubMed

Much progress has been made in the management of chronic-phase chronic myeloid leukemia (CP-CML), but there is a continuing imperative to develop curative treatments, predict patient responses to specific modalities, and anticipate disease relapse or progression. These needs underlie continuing interest in methods to detect and quantify the relevant leukemic cells in clinical samples with improved reliability and specificity. We report the results of comparing three methods to enumerate primitive CP-CML cells in the same samples: genotyping CD34(+)38(-) cells directly by fluorescence in situ hybridization, and measuring BCR-ABL1 transcript-genotyped colony-forming cell outputs in either 5-week long-term cultures (LTCs) containing non-engineered mouse fibroblasts or in 6-week LTCs containing mouse fibroblasts engineered to produce human Steel factor, granulocyte colony-stimulating factor, and IL-3. The results demonstrate that the first two methods significantly overestimate the prevalence of primitive CP-CML cells by comparison to the third. In additional studies, we found that CML-CD34(+) cells can repopulate the marrow and spleen of serially transplanted adult NOD/SCID-IL-2R? chain-null mice for more than 1 year with an almost exclusive myeloid differentiation in primary and secondary recipients and without evidence of disease progression. These findings underscore the importance of long-term functional in vitro and in vivo endpoints to identify and characterize CP-CML stem cells. PMID:23851302

Sloma, Ivan; Beer, Philip A; Saw, Kyi Min; Chan, Matthew; Leung, Donna; Raghuram, Kamini; Brimacombe, Cedric; Johnston, Bobby; Lambie, Karen; Forrest, Donna; Jiang, Xiaoyan; Eaves, Connie J

2013-07-11

59

Mobilization of CD34+CD38- hematopoietic stem cells after priming in acute myeloid leukemia  

PubMed Central

AIM: To evaluate quantitatively and qualitatively the different CD34+ cell subsets after priming by chemotherapy granulocyte colony-stimulating factor (± G-CSF) in patients with acute myeloid leukemia. METHODS: Peripheral blood and bone marrow samples were harvested in 8 acute myeloid leukemia patients during and after induction chemotherapy. The CD34/CD38 cell profile was analyzed by multi-parameter flow cytometry. Adhesion profile was made using CXC chemokine receptor 4 (CXCR4) (CD184), VLA-4 (CD49d/CD29) and CD47. RESULTS: Chemotherapy ± G-CSF mobilized immature cells (CD34+CD38? population), while the more mature cells (CD34+CD38low and CD34+CD38+ populations) decreased progressively after treatment. Circulating CD34+ cells tended to be more sensitive to chemotherapy after priming with G-CSF. CD34+ cell mobilization was correlated with a gradual increase in CXCR4 and CD47 expression, suggesting a role in cell protection and the capacity of homing back to the marrow. CONCLUSION: Chemotherapy ± G-CSF mobilizes into the circulation CD34+ bone marrow cells, of which, the immature CD34+CD38– cell population. Further manipulations of these interactions may be a means with which to control the trafficking of leukemia stem cells to improve patients’ outcomes.

Plesa, Adriana; Chelghoum, Youcef; Mattei, Eve; Labussiere, Helene; Elhamri, Mohamed; Cannas, Giovanna; Morisset, Stephane; Tagoug, Ines; Michallet, Mauricette; Dumontet, Charles; Thomas, Xavier

2013-01-01

60

The hematopoietic transcription factor PU.1 regulates RANK gene expression in myeloid progenitors  

SciTech Connect

Osteoclasts are bone resorbing cells of hematopoietic origin. The hematopoietic transcription factor PU.1 is critical for osteoclastogenesis; however, the molecular mechanisms of PU.1-regulated osteoclastogenesis have not been explored. Here, we present evidence that the receptor activator of nuclear factor {kappa}B (RANK) gene that has been shown to be crucial for osteoclastogenesis is a transcriptional target of PU.1. The PU.1 {sup -/-} progenitor cells failed to express the RANK gene and reconstitution of PU.1 in these cells induced RANK expression. Treatment of the PU.1 reconstituted cells with M-CSF and RANKL further augmented the RANK gene expression. To explore the regulatory mechanism of the RANK gene expression by PU.1, we have cloned the human RANK promoter. Transient transfection assays have revealed that the 2.2-kb RANK promoter was functional in a monocyte line RAW264.7, whereas co-transfection of PU.1 transactivated the RANK promoter in HeLa cells. Taken together, these results suggest that PU.1 regulates the RANK gene transcription and this may represent one of the key roles of PU.1 in osteoclast differentiation.

Kwon, Oh Hyung [Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Daejeon 305-333 (Korea, Republic of); Lee, Chong-Kil [College of Pharmacy, Chungbuk National University (Korea, Republic of); Lee, Young Ik [Liver Cell Signal Transduction Laboratory, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Daejeon 305-333 (Korea, Republic of); Paik, Sang-Gi [Department of Biology, School of Bioscience and Biotechnology, Chungnam National University (Korea, Republic of); Lee, Hyun-Jun [Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Daejeon 305-333 (Korea, Republic of)]. E-mail: hjlee7@kribb.re.kr

2005-09-23

61

Response of newly established mouse myeloid leukemic cell lines to MC3T3-G2/PA6 preadipocytes and hematopoietic factors  

SciTech Connect

Some mouse myeloid leukemias induced by X-irradiation and serially transplanted into syngenic mice do not proliferate in vitro even in the presence of hematopoietic factors. To examine whether such leukemic cells can proliferate in response to stromal cells, we cocultured them with MC3T3-G2/PA6 (PA6) preadipocytes, cells that can support the growth of hematopoietic stem cells. All leukemias developed into in vitro cell lines, showing a dependence on contact with the PA6 cells. Two cell lines responded to none of the known hematopoietic factors including interleukin-3 (IL-3), IL-4, IL-5, IL-6, GM-CSF, G-CSF, M-CSF, and Epo. These results demonstrate that the mechanism of the action of PA6 cells is different from that of any of the known hematopoietic factors, and that, because these two leukemic cell lines retained the ability to grow in vivo, responsiveness to the known hematopoietic factors is not essential for the leukemic cell growth in vivo. Furthermore, all leukemic cell lines could respond also to the preadipocytes fixed with formalin, paraformaldehyde, or glutaraldehyde, suggesting that some molecule(s) associated with the surface of PA6 cells or with extracellular matrix secreted by the preadipocytes is responsible for the leukemic cell growth.

Kodama, H.; Iizuka, M.; Tomiyama, T.; Yoshida, K.; Seki, M.; Suda, T.; Nishikawa, S. (Ohu Univ. School of Dentistry, Koriyama (Japan))

1991-01-01

62

Myeloid derived suppressor cells in transplantation.  

PubMed

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of hematopoietic derived cell precursors that can suppress immune responses in a variety of inflammatory settings. Here we review recent studies detailing expansion of phenotypically and functionally disparate MDSC. Findings related to MDSC accumulation, activation, and mechanisms utilized in immune suppression are presented. Further, we discuss recent reports that suggest MDSC are expanded during transplantation and that modulation of MDSC can participate in preventing graft rejection. PMID:21802931

Lees, Jason R; Azimzadeh, Agnes M; Bromberg, Jonathan S

2011-07-28

63

Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation.  

PubMed

Myeloid-derived suppressor cells (MDSCs) have emerged as a heterogeneic immunoregulatory population that can expand in response to inflammatory signals. Predominantly studied in cancer, MDSCs suppress T cells utilizing various mechanisms. In allogeneic hematopoietic stem cell transplantation (allo-HSCT) therapy-related toxicity and alloreactivity increase inflammatory cytokines that might favor an MDSC accumulation. To address this question, circulating CD14(+)HLA-DR(low/neg) cells were studied retrospectively in 51 allo-HSCT patients. These cells represent one of the few well-described human MDSC subsets under physiological and pathological conditions. The frequency of CD14(+)HLA-DR(low/neg) cells was significantly increased after allo-HSCT, especially in patients with acute graft-versus-host disease. Compared to healthy donor cells they were pSTAT1(low) (phosphorylated signal transducer and activator of transcription) and indoleamine 2,3-dioxygenase (IDO)(high). Serum levels of granulocyte colony-stimulating factor and interleukin-6, which both have been linked to MDSC induction, correlated positively with the frequency of CD14(+)HLA-DR(low/neg) cells. In vitro dysfunction of patient T cells, such as reduced proliferative capacity or CD3?-chain expression, was rescued by blocking the IDO activity of CD14(+)HLA-DR(low/neg) cells. Overall, we identified a T-cell-suppressive monocytic population that expands after allo-HSCT. The mechanisms responsible for such accumulation remain to be elucidated. It will be of great interest to prospectively investigate the influence of these cells on the graft-versus-tumor and -host reaction. PMID:22828446

Mougiakakos, D; Jitschin, R; von Bahr, L; Poschke, I; Gary, R; Sundberg, B; Gerbitz, A; Ljungman, P; Le Blanc, K

2012-07-25

64

Density of Gr1-positive myeloid precursor cells, p-STAT3 expression and gene expression pattern in canine mammary cancer metastasis  

Microsoft Academic Search

The very recent studies on human and mice models have indicated an important role of myeloid precursor cells (progenitors\\u000a or not fully differentiated cells that express the Gr1 antigen also called Gr1-positive myeloid suppressor cells) in the tumor\\u000a progression and metastasis. They are thought to suppress the immune system and promote angiogenesis via Signal transducer\\u000a and activator of transcription 3

Magdalena Król; Karol M. Paw?owski; Izabella Dolka; Olga Musielak; Kinga Majchrzak; Joanna Mucha; Tomasz Motyl

65

New experimental and theoretical investigations of hematopoietic stem cells and chronic myeloid leukemia.  

PubMed

We report on a focused workshop of The Leukemia and Lymphoma Society that was held at Goldsmiths, University of London in 2008. During this workshop we discussed new clinical and experimental data in chronic myeloid leukemia (CML) research, particularly focusing on the validity (or otherwise) of corresponding mathematical models and simulations. We were specifically interested in whether the models could shed light on any of the fundamental mechanisms underlying this disease. Moreover, we were aiming to form a new community of clinicians and modelers looking at this disease and to define a common language and theoretical framework within which collaboration could flourish. The workshop showed the role that models can play, not just in trying to fit to existing data or predicting what individual mechanisms or system behaviors might occur, but also in challenging the orthodoxy of the concept of a stem cell and concepts such as "differentiation" and "determination". For years the prevailing view of a stem cell has been an entity (object) with a fixed set of behaviors and with a pre-determined fate. New perspectives in modeling, coupled with the new data that are being accumulated in the genesis of CML and its treatment, questions these assumptions. We propose how we can reach a consensus about a functional view of stem cells in a more continuous and flexible way and how, within this context, we can investigate the significance of modeling results and how they might impact on our interpretation of experimental observations and the development of new clinical strategies. This paper reports on the workshop and the state-of-the-art models and data from experimental and clinical trials, and sets out a roadmap for more interdisciplinary collaboration between modelers, wet-lab experimentalists, and clinicians interested in CML. It is our strong belief that a more integrated and coherent interdisciplinary approach will further advance the treatment of CML in future years. PMID:19411181

Roeder, Ingo; d'Inverno, Mark

2009-05-02

66

Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells  

PubMed Central

One mechanism for disrupting the MLL gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is through partial tandem duplication (MLL-PTD); however, the mechanism by which MLL-PTD contributes to MDS and AML development and maintenance is currently unknown. Herein, we investigated hematopoietic stem/progenitor cell (HSPC) phenotypes of Mll-PTD knock-in mice. Although HSPCs (Lin?Sca1+Kit+ (LSK)/SLAM+ and LSK) in MllPTD/WT mice are reduced in absolute number in steady state because of increased apoptosis, they have a proliferative advantage in colony replating assays, CFU-spleen assays, and competitive transplantation assays over wild-type HSPCs. The MllPTD/WT-derived phenotypic short-term (ST)–HSCs/multipotent progenitors and granulocyte/macrophage progenitors have self-renewal capability, rescuing hematopoiesis by giving rise to long-term repopulating cells in recipient mice with an unexpected myeloid differentiation blockade and lymphoid-lineage bias. However, MllPTD/WT HSPCs never develop leukemia in primary or recipient mice, suggesting that additional genetic and/or epigenetic defects are necessary for full leukemogenic transformation. Thus, the Mll-PTD aberrantly alters HSPCs, enhances self-renewal, causes lineage bias, and blocks myeloid differentiation. These findings provide a framework by which we can ascertain the underlying pathogenic role of MLL-PTD in the clonal evolution of human leukemia, which should facilitate improved therapies and patient outcomes.

Zhang, Yue; Yan, Xiaomei; Sashida, Goro; Zhao, Xinghui; Rao, Yalan; Goyama, Susumu; Whitman, Susan P.; Zorko, Nicholas; Bernot, Kelsie; Conway, Rajeana M.; Witte, David; Wang, Qian-fei; Tenen, Daniel G.; Xiao, Zhijian; Marcucci, Guido; Mulloy, James C.; Grimes, H. Leighton; Caligiuri, Michael A.

2012-01-01

67

Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on SHP2 phosphatase function.  

PubMed

The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of-function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of-function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity. PMID:23082805

Broxmeyer, Hal E; Etienne-Julan, Maryse; Gotoh, Akihiko; Braun, Stephen E; Lu, Li; Cooper, Scott; Feng, Gen-Sheng; Li, Xing Jun; Chan, Rebecca J

2012-12-16

68

The earliest intrathymic precursors of CD8?(+) thymic dendritic cells correspond to myeloid-type double-negative 1c cells.  

PubMed

The dendritic cells (DCs) present in lymphoid and non-lymphoid organs are generated from progenitors with myeloid-restricted potential. However, in the thymus a major subset of DCs expressing CD8? and langerin (CD207) appears to stand apart from all other DCs in that it is thought to derive from progenitors with lymphoid potential. Using mice expressing a fluorescent reporter and a diphtheria toxin receptor under the control of the cd207 gene, we demonstrated that CD207(+) CD8?(+) thymic DCs do not share a common origin with T cells but originate from intrathymic precursors that express markers that are normally present on all (CD11c(+) and MHCII molecules) or on some (CD207, CD135, CD8?, CX3CR1) DC subsets. Those intrathymic myeloid-type precursors correspond to CD44(+) CD25(-) double-negative 1c (DN1c) cells and are continuously renewed from bone marrow-derived canonical DC precursors. In conclusion, our results demonstrate that the earliest intrathymic precursors of CD8?(+) thymic DCs correspond to myeloid-type DN1c cells and support the view that under physiological conditions myeloid-restricted progenitors generate the whole constellation of DCs present in the body including the thymus. PMID:21630253

Luche, Hervé; Ardouin, Laurence; Teo, Pearline; See, Peter; Henri, Sandrine; Merad, Miriam; Ginhoux, Florent; Malissen, Bernard

2011-07-04

69

Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease  

PubMed Central

Mature myeloid cells (macrophages and CD11b+ dendritic cells) form a prominent component of neuroinflammatory infiltrates in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). The mechanism by which these cells are replenished during relapsing and chronic neuroinflammation is poorly understood. Here we demonstrate that CD11b+CD62L+Ly6Chi monocytes with colony-forming potential are mobilized into the bloodstream by a granulocyte-macrophage colony-stimulating factor-dependent pathway immediately before EAE relapses. Circulating Ly6Chi monocytes traffic across the blood-brain barrier, up-regulate proinflammatory molecules, and differentiate into central nervous system dendritic cells and macrophages. Enrichment of Ly6Chi monocytes in the circulating pool is associated with an earlier onset and increased severity of clinical EAE. Our studies indicate that granulocyte-macrophage colony-stimulating factor–driven release of Ly6Chi precursors from the bone marrow prevents exhaustion of central nervous system myeloid populations during relapsing or chronic autoimmune demyelination, suggesting a novel pathway for therapeutic targeting.

King, Irah L.; Dickendesher, Travis L.

2009-01-01

70

MicroRNA-150 Expression Induces Myeloid Differentiation of Human Acute Leukemia Cells and Normal Hematopoietic Progenitors.  

PubMed

In acute myeloid leukemia (AML) and blast crisis (BC) chronic myeloid leukemia (CML) normal differentiation is impaired. Differentiation of immature stem/progenitor cells is critical for normal blood cell function. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that interfere with gene expression by degrading messenger RNAs (mRNAs) or blocking protein translation. Aberrant miRNA expression is a feature of leukemia and miRNAs also play a significant role in normal hematopoiesis and differentiation. We have identified miRNAs differentially expressed in AML and BC CML and identified a new role for miR-150 in myeloid differentiation. Expression of miR-150 is low or absent in BC CML and AML patient samples and cell lines. We have found that expression of miR-150 in AML cell lines, CD34+ progenitor cells from healthy individuals, and primary BC CML and AML patient samples at levels similar to miR-150 expression in normal bone marrow promotes myeloid differentiation of these cells. MYB is a direct target of miR-150, and we have identified that the observed phenotype is partially mediated by MYB. In AML cell lines, differentiation of miR-150 expressing cells occurs independently of retinoic acid receptor ? (RARA) signaling. High-throughput gene expression profiling (GEP) studies of the AML cell lines HL60, PL21, and THP-1 suggest that activation of CEPBA, CEBPE, and cytokines associated with myeloid differentiation in miR-150 expressing cells as compared to control cells contributes to myeloid differentiation. These data suggest that miR-150 promotes myeloid differentiation, a previously uncharacterized role for this miRNA, and that absent or low miR-150 expression contributes to blocked myeloid differentiation in acute leukemia cells. PMID:24086639

Morris, Valerie A; Zhang, Ailin; Yang, Taimei; Stirewalt, Derek L; Ramamurthy, Ranjani; Meshinchi, Soheil; Oehler, Vivian G

2013-09-24

71

MicroRNA-150 Expression Induces Myeloid Differentiation of Human Acute Leukemia Cells and Normal Hematopoietic Progenitors  

PubMed Central

In acute myeloid leukemia (AML) and blast crisis (BC) chronic myeloid leukemia (CML) normal differentiation is impaired. Differentiation of immature stem/progenitor cells is critical for normal blood cell function. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that interfere with gene expression by degrading messenger RNAs (mRNAs) or blocking protein translation. Aberrant miRNA expression is a feature of leukemia and miRNAs also play a significant role in normal hematopoiesis and differentiation. We have identified miRNAs differentially expressed in AML and BC CML and identified a new role for miR-150 in myeloid differentiation. Expression of miR-150 is low or absent in BC CML and AML patient samples and cell lines. We have found that expression of miR-150 in AML cell lines, CD34+ progenitor cells from healthy individuals, and primary BC CML and AML patient samples at levels similar to miR-150 expression in normal bone marrow promotes myeloid differentiation of these cells. MYB is a direct target of miR-150, and we have identified that the observed phenotype is partially mediated by MYB. In AML cell lines, differentiation of miR-150 expressing cells occurs independently of retinoic acid receptor ? (RARA) signaling. High-throughput gene expression profiling (GEP) studies of the AML cell lines HL60, PL21, and THP-1 suggest that activation of CEPBA, CEBPE, and cytokines associated with myeloid differentiation in miR-150 expressing cells as compared to control cells contributes to myeloid differentiation. These data suggest that miR-150 promotes myeloid differentiation, a previously uncharacterized role for this miRNA, and that absent or low miR-150 expression contributes to blocked myeloid differentiation in acute leukemia cells.

Morris, Valerie A.; Zhang, Ailin; Yang, Taimei; Stirewalt, Derek L.; Ramamurthy, Ranjani; Meshinchi, Soheil; Oehler, Vivian G.

2013-01-01

72

Clonality analysis of hematopoietic cell lineages in acute myeloid leukemia and translocation (8;21): only myeloid cells are part of the malignant clone  

Microsoft Academic Search

Bone marrow from six patients with acute myeloid leukemia (AML) and t(8;21) (q22;q22) or a variant t(8;13;21) was studied by simultaneous analysis of cell morphology and karyotype. Combination of May–Grünwald–Giemsa (MGG) and fluorescence in situ hybridization (FISH) using probes specific for the breakpoint regions of chromosome 8 and 21 allowed us to establish the extent of cell-lineage involvement of the

K van Lom; A Hagemeijer; F Vandekerckhove; GE de Greef; N Sacchi; B Löwenberg

1997-01-01

73

Characteristics of myeloid differentiation and maturation pathway derived from human hematopoietic stem cells exposed to different linear energy transfer radiation types.  

PubMed

Exposure of hematopoietic stem/progenitor cells (HSPCs) to ionizing radiation causes a marked suppression of mature functional blood cell production in a linear energy transfer (LET)- and/or dose-dependent manner. However, little information about LET effects on the proliferation and differentiation of HSPCs has been reported. With the aim of characterizing the effects of different types of LET radiations on human myeloid hematopoiesis, in vitro hematopoiesis in Human CD34(+) cells exposed to carbon-ion beams or X-rays was compared. Highly purified CD34(+) cells exposed to each form of radiation were plated onto semi-solid culture for a myeloid progenitor assay. The surviving fractions of total myeloid progenitors, colony-forming cells (CFC), exposed to carbon-ion beams were significantly lower than of those exposed to X-rays, indicating that CFCs are more sensitive to carbon-ion beams (D(0) = 0.65) than to X-rays (D(0) = 1.07). Similar sensitivities were observed in granulocyte-macrophage and erythroid progenitors, respectively. However, the sensitivities of mixed-type progenitors to both radiation types were similar. In liquid culture for 14 days, no significant difference in total numbers of mononuclear cells was observed between non-irradiated control culture and cells exposed to 0.5 Gy X-rays, whereas 0.5 Gy carbon-ion beams suppressed cell proliferation to 4.9% of the control, a level similar to that for cells exposed to 1.5 Gy X-rays. Cell surface antigens associated with terminal maturation, such as CD13, CD14, and CD15, on harvest from the culture of X-ray-exposed cells were almost the same as those from the non-irradiated control culture. X-rays increased the CD235a(+) erythroid-related fraction, whereas carbon-ion beams increased the CD34(+)CD38(-) primitive cell fraction and the CD13(+)CD14(+/-)CD15(-) fraction. These results suggest that carbon-ion beams inflict severe damage on the clonal growth of myeloid HSPCs, although the intensity of cell surface antigen expression by mature myeloid cells derived from HSPCs exposed to each type of radiation was similar to that by controls. PMID:23555027

Monzen, Satoru; Yoshino, Hironori; Kasai-Eguchi, Kiyomi; Kashiwakura, Ikuo

2013-03-12

74

Reduced intensity conditioning allows for up-front allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in newly-diagnosed high-risk acute myeloid leukemia.  

PubMed

There is substantial need to improve the outcome of patients with high-risk acute myeloid leukemia (AML). The clinical trial reported here investigated a new approach of up-front allogeneic hematopoietic stem cell transplantation (HSCT), provided a median of 40 days (range 22-74) after diagnosis, in twenty-six consecutive patients with newly-diagnosed high-risk AML characterized by poor-risk cytogenetics (n = 19) or inadequate blast clearance by induction chemotherapy (IC, n = 7). The median age was 49 years (range 17-68). During IC-induced aplasia after the 1st (n = 11) or 2nd (n = 15) cycle, patients received allogeneic peripheral blood stem cells (PBSC) from related (n = 11) or unrelated (n = 15) donors following a fludarabine-based reduced-intensity regimen. Seventeen patients were not in remission before HSCT with a median marrow blast count of 34% (range 6-70). All patients achieved rapid engraftment and went into remission with complete myeloid and lymphatic chimerism. Grades II to IV acute GvHD occurred in 14 (56%) and extensive chronic GvHD was documented in 8 (35%) patients. The probability of disease-free survival was 61% with only three patients relapsing 5, 6 and 7 months after transplantation, respectively. Up-front allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in high-risk AML patients and warrants further investigation. PMID:16482208

Platzbecker, U; Thiede, C; Füssel, M; Geissler, G; Illmer, T; Mohr, B; Hänel, M; Mahlberg, R; Krümpelmann, U; Weissinger, F; Schaich, M; Theuser, C; Ehninger, G; Bornhäuser, M

2006-04-01

75

Distinct regulation of c-myb gene expression by HoxA9, Meis1 and Pbx proteins in normal hematopoietic progenitors and transformed myeloid cells  

PubMed Central

The proto-oncogenic protein c-Myb is an essential regulator of hematopoiesis and is frequently deregulated in hematological diseases such as lymphoma and leukemia. To gain insight into the mechanisms underlying the aberrant expression of c-Myb in myeloid leukemia, we analyzed and compared c-myb gene transcriptional regulation using two cell lines modeling normal hematopoietic progenitor cells (HPCs) and transformed myelomonocytic blasts. We report that the transcription factors HoxA9, Meis1, Pbx1 and Pbx2 bind in vivo to the c-myb locus and maintain its expression through different mechanisms in HPCs and leukemic cells. Our analysis also points to a critical role for Pbx2 in deregulating c-myb expression in murine myeloid cells cotransformed by the cooperative activity of HoxA9 and Meis1. This effect is associated with an intronic positioning of epigenetic marks and RNA polymerase II binding in the orthologous region of a previously described alternative promoter for c-myb. Taken together, our results could provide a first hint to explain the abnormal expression of c-myb in leukemic cells.

Dasse, E; Volpe, G; Walton, D S; Wilson, N; Del Pozzo, W; O'Neill, L P; Slany, R K; Frampton, J; Dumon, S

2012-01-01

76

Do Hematopoietic Cells Exposed to a Neurogenic Environment Mimic Properties of Endogenous Neural Precursors?  

PubMed Central

Hematopoietic progenitors are cells, which under challenging experimental conditions can develop unusual phenotypic properties, rather distant from their original mesodermal origin. As previously reported, cells derived from human umbilical cord blood (HUCB) or human bone marrow (BM) under certain in vivo or in vitro conditions can manifest neural features that resemble features of neural-derived cells, immunocytochemically and in some instances also morphologically. The present study explored how hematopoietic-derived cells would respond to neurogenic signals from the subventricular zone (SVZ) of adult and aged (6 and 16 months old) rats. The mononuclear fraction of HUCB cells was transplanted into the SVZ of immunosuppressed (single cyclosporin or three-drug treatment) animals. The triple-suppression paradigm allowed us to protect transplanted human cells within the brain and to explore further their phenotypic and migratory properties. One week after implantation, many surviving HUCB cells were located within the SVZ and the vertical limb of the rostral migratory stream (RMS). The migration of HUCB cells was restricted exclusively to the pathway leading to the olfactory bulb. In younger animals, grafted cells navigated almost halfway through the vertical limb, whereas, in the older animals, the migration was less pronounced. The overall cell survival was greater in younger animals than in older ones. Immunocytochemistry for surface CD antigen expression showed that many HUCB cells, either cultured or within the brain parenchyma, retained their hematopoietic identity. A few cells, identified by using human-specific antibodies (anti-human nuclei, or mitochondria) expressed nestin and doublecortin, markers of endogenous neural progenitors. Therefore, it is believed that the environment of the neurogenic SVZ, even in aged animals, was able to support survival, “neuralization,” and migratory features of HUCB-derived cells.

Walczak, P.; Chen, N.; Hudson, J.E.; Willing, A.E.; Garbuzova-Davis, S.N.; Song, S.; Sanberg, P.R.; Sanchez-Ramos, J.; Bickford, P.C.; Zigova, T.

2006-01-01

77

In vivo radiosensitivity and recovery pattern of the hematopoietic precursor cells and stem cells in mouse bone marrow  

SciTech Connect

Survival curves were determined for colony-forming hematopoietic stem cells (CFU-Mix and CFU-S10) as well as precursor cells (CFU-E, CFU-C, CFU-F, and BFU-E) in bone marrow of the mouse at various times up to 4 weeks after whole-body irradiation (1.5 or 3.0 Gy) in order to elucidate in vivo radiosensitivity and recovery patterns. These measurements represented the first attempts to examine CFU-Mix simultaneously with the other cell populations. CFU-E (D0 = 53 rad) and BFU-E (D0 = 68 rad) were the most radiosensitive. CFU-S10 (D0 = 81 rad) had intermediate radiosensitivity. CFU-Mix (D0 = 144 rad) and CFU-C (D0 = 157 rad) were relatively radioresistant. CFU-F (D0 = 257 rad) was the most radioresistant. The precursor and stem cells could be classified into three groups based on the recovery pattern. The first group, consisting of CFU-Mix, BFU-E, and CFU-S10, showed very slow recovery and did not reach normal levels even after day 28. CFU-E, the second group, showed the most severe depletion immediately after irradiation, and recovered most quickly with an overshoot at day 5. CFU-C and CFU-F cells, forming the third group, decreased more gradually and slightly, and recovered to the normal level after a transient rise by day 10-14.

Imai, Y.; Nakao, I.

1987-09-01

78

Natural killer-cell differentiation by myeloid progenitors  

PubMed Central

Because lymphoid progenitors can give rise to natural killer (NK) cells, NK ontogeny has been considered to be exclusively lymphoid. Here, we show that rare human CD34+ hematopoietic progenitors develop into NK cells in vitro in the presence of cytokines (interleukin-7, interleukin-15, stem cell factor, and fms-like tyrosine kinase-3 ligand). Adding hydrocortisone and stromal cells greatly increases the frequency of progenitor cells that give rise to NK cells through the recruitment of myeloid precursors, including common myeloid progenitors and granulocytic-monocytic precursors to the NK-cell lineage. WNT signaling was involved in this effect. Cells at more advanced stages of myeloid differentiation (with increasing expression of CD13 and macrophage colony-stimulating factor receptor [M-CSFR]) could also differentiate into NK cells in the presence of cytokines, stroma, and hydrocortisone. NK cells derived from myeloid precursors (CD56?CD117+M-CSFR+) showed more expression of killer immunoglobulin-like receptors, a fraction of killer immunoglobulin–like receptor-positive–expressing cells that lacked NKG2A, a higher cytotoxicity compared with CD56?CD117+M-CSFR? precursor-derived NK cells and thus resemble the CD56dim subset of NK cells. Collectively, these studies show that NK cells can be derived from the myeloid lineage.

Grzywacz, Bartosz; Kataria, Nandini; Kataria, Niketa; Blazar, Bruce R.; Miller, Jeffrey S.

2011-01-01

79

Methods of inhibiting hematopoietic stem cells using human myeloid progenitor inhibitory factor-1 (MPIF-1) (Ckbeta-8/MIP-3)  

US Patent & Trademark Office Database

There are disclosed therapeutic compositions and methods using isolated nucleic acid molecules encoding a human myeloid progenitor inhibitory factor-1 (MPIF-1) polypeptide (previously termed MIP-3 and chemokine .beta.8 (CK.beta.8 or ckb-8)), as well as MPIF-1 polypeptide itself, as are vectors, host cells and recombinant methods for producing the same.

2002-12-17

80

Human CD34Derived Myeloid Dendritic Cell Development Requires Intact Phosphatidylinositol 3-Kinase-Protein Kinase B-Mammalian Target of Rapamycin Signaling  

Microsoft Academic Search

Dendritic cells (DCs) are composed of different subsets that exhibit distinct functionality in the induction and regulation of immune responses. The myeloid DC subsets, including interstitial DCs and Langerhans cells (LCs), develop from CD34(+) hematopoietic progenitors via direct DC precursors or monocytes. The molecular mechanisms regulating DC development are still largely unknown and mostly studied in mice. Phosphatidylinositol 3-kinase (PI3K)

Laar van de L; M. Buitenhuis; Wensveen van F. M; H. L. A. Janssen; P. J. Coffer; A. M. Woltman

2010-01-01

81

Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome  

Microsoft Academic Search

Hematopoietic stem cells sequentially pass through a series of decision points affecting self-renewal or lineage-specific differentiation. Notch1 receptor is a known modulator of lineage-specific events in hematopoiesis that we assessed in the context of in vivo stem cell kinetics. Us- ing RAG-12\\/2 mouse stems cells, we docu- mented increased stem cell numbers due to decreased differentiation and enhanced stem cell

Sebastian Stier; Tao Cheng; David Dombkowski; Nadia Carlesso; David T. Scadden

2002-01-01

82

Long-term outcomes in patients with high-risk myeloid malignancies following matched related donor hematopoietic cell transplantation with myeloablative conditioning of BU, etoposide and CY.  

PubMed

Patients with high-risk or advanced myeloid malignancies have limited effective treatment options. These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT). We report a single-institution, long-term follow-up of 96 patients, median age 50 (range, 20-60) years, who received HLA-matched related HCT between 1992 and 2007. All patients were treated with a uniform preparatory regimen intended to enhance the widely used regimen of BU and CY that included: BU 16.0?mg/kg (days -8 to -5), etoposide 60?mg/kg (day -4), CY 60?mg/kg (day -2) with GVHD prophylaxis of CsA or FK506 and prednisone. Disease status at transplantation was high-risk AML (n=41), CML in second chronic phase or blast crisis (n=8), myelofibrosis and myeloproliferative disorders (n=8), and myelodysplasia (n=39). Thirty-six percent (n=35) of patients received BM whereas 64% (n=61) received G-CSF-mobilized PBPC. With a median follow-up of 5.6 years (range, 1.6-14.6 years) actuarial 5-year OS was 32% (95% CI 22-42) and 5-year EFS was 31% (95% CI 21-41). Relapse rate was 24% (95% CI 15-33) at 2 and 5 years. Nonrelapse mortality was 29% (95% CI 20-38) at day 100 and 38% (95% CI 29-47) at 1 year. Cumulative incidence of acute (grade II-IV) and extensive chronic GVHD was 27% (95% CI 18-36) and 29% (95% CI 18-40), respectively. There was no statistically significant difference in OS (31 vs 32%, P=0.89) or relapse rates (17 vs 28%, P=0.22) for recipients of BM vs PBPC, respectively. These results confirm that patients with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning. PMID:20498648

Naik, S; Wong, R; Arai, S; Brown, J; Laport, G; Lowsky, R; Miklos, D; Shizuru, J; Blume, K; Negrin, R; Johnston, L

2010-05-24

83

Manganese superoxide dismutase depletion in murine hematopoietic stem cells perturbs iron homeostasis, globin switching, and epigenetic control in erythrocyte precursor cells.  

PubMed

Heme synthesis partially occurs in the mitochondrial matrix; thus there is a high probability that enzymes and intermediates important in the production of heme will be exposed to metabolic by-products including reactive oxygen species. In addition, the need for ferrous iron for heme production, Fe/S coordination, and other processes occurring in the mitochondrial matrix suggests that aberrant fluxes of reactive oxygen species in this compartment might perturb normal iron homeostasis. Manganese superoxide dismutase (Sod2) is an antioxidant enzyme that governs steady-state levels of the superoxide in the mitochondrial matrix. Using hematopoietic stem cell-specific conditional Sod2 knockout mice we observed increased superoxide concentrations in red cell progeny, which caused significant pathologies including impaired erythrocytes and decreased ferrochelatase activity. Animals lacking Sod2 expression in erythroid precursors also displayed extramedullary hematopoiesis and systemic iron redistribution. Additionally, the increase in superoxide flux in erythroid precursors caused abnormal gene regulation of hematopoietic transcription factors, globins, and iron-response genes. Moreover, the erythroid precursors also displayed evidence of global changes in histone posttranslational modifications, a likely cause of at least some of the aberrant gene expression noted. From a therapeutic translational perspective, mitochondrially targeted superoxide-scavenging antioxidants partially rescued the observed phenotype. Taken together, our findings illuminate the superoxide sensitivity of normal iron homeostasis in erythrocyte precursors and suggest a probable link between mitochondrial redox metabolism and epigenetic control of nuclear gene regulation during mammalian erythropoiesis. PMID:23219873

Case, Adam J; Madsen, Joshua M; Motto, David G; Meyerholz, David K; Domann, Frederick E

2012-12-05

84

Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation  

PubMed Central

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.

Capotondo, Alessia; Milazzo, Rita; Politi, Letterio Salvatore; Quattrini, Angelo; Palini, Alessio; Plati, Tiziana; Merella, Stefania; Nonis, Alessandro; di Serio, Clelia; Montini, Eugenio; Naldini, Luigi; Biffi, Alessandra

2012-01-01

85

Impact of Cranial Irradiation Added to Intrathecal Conditioning in Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia With Central Nervous System Involvement  

SciTech Connect

Purpose: Neither the prognostic importance nor the appropriate management of central nervous system (CNS) involvement is known for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We examined the impact of a CNS irradiation boost to standard intrathecal chemotherapy (ITC). Methods and Materials: From 1995 to 2005, a total of 648 adult AML patients received a myeloablative HCT: 577 patients were CNS negative (CNS-), and 71 were CNS positive (CNS+). Of the 71 CNS+ patients, 52 received intrathecal chemotherapy alone (CNS+ITC), and 19 received ITC plus an irradiation boost (CNS+RT). Results: The CNS-, CNS+ITC, and CNS+RT patients had 1- and 5-year relapse-free survivals (RFS) of 43% and 35%, 15% and 6%, and 37% and 32%, respectively. CNS+ITC patients had a statistically significant worse RFS compared with CNS- patients (hazard ratio [HR], 2.65; 95% confidence interval [CI], 2.0-3.6; p < 0.0001). CNS+RT patients had improved relapse free survival over that of CNS+ITC patients (HR, 0.45; 95% CI, 0.2-0.8; p = 0.01). The 1- and 5-year overall survivals (OS) of patients with CNS-, CNS+ITC, and CNS+RT, were 50% and 38%, 21% and 6%, and 53% and 42%, respectively. The survival of CNS+RT were significantly better than CNS+ITC patients (p = 0.004). After adjusting for known risk factors, CNS+RT patients had a trend toward lower relapse rates and reduced nonrelapse mortality. Conclusions: CNS+ AML is associated with a poor prognosis. The role of a cranial irradiation boost to intrathecal chemotherapy appears to mitigate the risk of CNS disease, and needs to be further investigated to define optimal treatment strategies.

Mayadev, Jyoti S. [Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA (United States); Department of Radiation Oncology University of California-Davis Medical Center, Davis, CA (United States); Douglas, James G., E-mail: drjay@u.washington.ed [Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA (United States); Department of Pediatrics, University of Washington School of Medicine, Seattle, WA (United States); Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA (United States); Storer, Barry E. [University of Washington School of Public Health, Seattle, WA (United States); Fred Hutchinson Cancer Research Center, Seattle, WA (United States); Appelbaum, Frederick R.; Storb, Rainer [Department of Medicine, University of Washington School of Medicine, Seattle, WA (United States); Fred Hutchinson Cancer Research Center, Seattle, WA (United States)

2011-05-01

86

Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase  

PubMed Central

Purpose Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. Patients and Methods Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen–matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. Results Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). Conclusion Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population.

Goldman, John M.; Majhail, Navneet S.; Klein, John P.; Wang, Zhiwei; Sobocinski, Kathleen A.; Arora, Mukta; Horowitz, Mary M.; Rizzo, J. Douglas

2010-01-01

87

The human placenta is a hematopoietic organ during the embryonic and fetal periods of development  

PubMed Central

We studied the potential role of the human placenta as a hematopoietic organ during embryonic and fetal development. Placental samples contained two cell populations—CD34++CD45low and CD34+CD45low—that were found in chorionic villi and in the chorioamniotic membrane. CD34++CD45low cells express many cell surface antigens found on multipotent primitive hematopoietic progenitors and hematopoietic stem cells. CD34++CD45low cells contained colony-forming units culture (CFU-C) with myeloid and erythroid potential in clonogenic in vitro assays, and they generated CD56+ natural killer cells and CD19+CD20+sIgM+ B cells in polyclonal liquid cultures. CD34+CD45low cells mostly comprised erythroid- and myeloid-committed progenitors, while CD34? cells lacked CFU-C. The placenta-derived precursors were fetal in origin, as demonstrated by FISH using repeat-sequence chromosome-specific probes for X and Y. The number of CD34++CD45low cells increased with gestational age, but their density (cells per gram of tissue) peaked at 5–8 wk, decreasing more than sevenfold at the onset of the fetal phase (9 wk of gestation). In addition to multipotent progenitors, the placenta contained myeloid- and erythroid-committed progenitors indicative of active in situ hematopoiesis. These data suggest that the human placenta is an important hematopoietic organ, raising the possibility of banking placental hematopoietic stem cells along with cord blood for transplantation.

Barcena, Alicia; Kapidzic, Mirhan; Muench, Marcus O.; Gormley, Matthew; Scott, Marvin A.; Weier, Jingly F.; Ferlatte, Christy; Fisher, Susan J.

2008-01-01

88

CD133 is a modifier of hematopoietic progenitor frequencies but is dispensable for the maintenance of mouse hematopoietic stem cells  

PubMed Central

Pentatransmembrane glycoprotein prominin-1 (CD133) is expressed at the cell surface of multiple somatic stem cells, and it is widely used as a cell surface marker for the isolation and characterization of human hematopoietic stem cells (HSCs) and cancer stem cells. CD133 has been linked on a cell biological basis to stem cell-fate decisions in human HSCs and emerges as an important physiological regulator of stem cell maintenance and expansion. Its expression and physiological relevance in the murine hematopoietic system is nevertheless elusive. We show here that CD133 is expressed by bone marrow-resident murine HSCs and myeloid precursor cells with the developmental propensity to give rise to granulocytes and monocytes. However, CD133 is dispensable for the pool size and function of HSCs during steady-state hematopoiesis and after transplantation, demonstrating a substantial species difference between mouse and man. Blood cell numbers in the periphery are normal; however, CD133 appears to be a modifier for the development of growth-factor responsive myeloerythroid precursor cells in the bone marrow under steady state and mature red blood cells after hematopoietic stress. Taken together, these studies show that CD133 is not a critical regulator of hematopoietic stem cell function in mouse but that it modifies frequencies of growth-factor responsive hematopoietic progenitor cells during steady state and after myelotoxic stress in vivo.

Arndt, Kathrin; Grinenko, Tatyana; Mende, Nicole; Reichert, Doreen; Portz, Melanie; Ripich, Tatsiana; Carmeliet, Peter; Corbeil, Denis; Waskow, Claudia

2013-01-01

89

Generation of functional antigen-specific T cells in defined genetic backgrounds by retrovirus-mediated expression of TCR cDNAs in hematopoietic precursor cells  

PubMed Central

We have developed an alternative to transgenesis for producing antigen-specific T cells in vivo. In this system, clonal naive T cells with defined antigen specificity are generated by retrovirus-mediated expression of T cell antigen receptor cDNAs in RAG1-deficient murine hematopoietic precursor cells. These T cells can be stimulated to proliferate and produce cytokines by exposure to antigen in vitro, and they become activated and expand in vivo after immunization. IL-2-deficient T cells generated by this technique show decreased proliferation and cytokine production, both of which can be rescued by exogenous addition of this growth factor. Thus, retrovirus-mediated expression of T cell antigen receptor cDNAs in hematopoietic precursor cells permits the rapid and efficient analysis of the life history of antigen-specific T cells in different genetic backgrounds and may allow for the long-term production of antigen-specific T cells with different functional properties for prophylactic and therapeutic purposes.

Yang, Lili; Qin, Xiao-Feng; Baltimore, David; Van Parijs, Luk

2002-01-01

90

Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera.  

PubMed

In the current model of the pathogenesis of polycythemia vera (PV), the JAK2V617F mutation arises in hematopoietic stem cells (HSCs) that maintain the disease, while erythroid precursor populations expand, resulting in excessive red blood cell production. We examined the role of these specific cell populations using a conditional Jak2V617F knockin murine model. We demonstrate that the most immature long-term (LT) HSCs are solely responsible for initiating and maintaining the disease in vivo and that Jak2V617F mutant LT-HSCs dominate hematopoiesis over time. When we induced Jak2V617F expression in erythropoietin receptor expressing precursor cells, the mice developed elevated hematocrit, expanded erythroid precursors, and suppressed erythropoietin levels. However, the disease phenotype was significantly attenuated compared with mice expressing Jak2V617F in LT-HSCs. In addition to developing a PV phenotype, all mice transplanted with Jak2V617F LT-HSCs underwent myelofibrotic transformation over time. These findings recapitulate the development of post-PV myelofibrosis in human myeloproliferative neoplasms. In aggregate, these results demonstrate the distinct roles of LT-HSCs and erythroid precursors in the pathogenesis of PV. PMID:22627765

Mullally, Ann; Poveromo, Luke; Schneider, Rebekka K; Al-Shahrour, Fatima; Lane, Steven W; Ebert, Benjamin L

2012-05-24

91

Myeloid-derived suppressor cells: mechanisms of action and recent advances in their role in transplant tolerance  

PubMed Central

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature hematopoietic precursors known to suppress immune responses in infection, chronic inflammation, cancer, and autoimmunity. In this paper, we review recent findings detailing their mode of action and discuss recent reports that suggest that MDSC are also expanded during transplantation and that modulation of MDSC can participate in preventing graft rejection as well as graft-versus-host disease.

Dilek, Nahzli; Vuillefroy de Silly, Romain; Blancho, Gilles; Vanhove, Bernard

2012-01-01

92

NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights.  

PubMed

Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodomain proteins, and at least 5 NUP98 fusions involve known histone-modifying genes. Several of the NUP98 fusions, including NUP98-homeobox (HOX)A9, NUP98-HOXD13, and NUP98-JARID1A, have been used to generate animal models of both lymphoid and myeloid malignancy; these models typically up-regulate HOXA cluster genes, including HOXA5, HOXA7, HOXA9, and HOXA10. In addition, several of the NUP98 fusion proteins have been shown to inhibit differentiation of hematopoietic precursors and to increase self-renewal of hematopoietic stem or progenitor cells, providing a potential mechanism for malignant transformation. PMID:21948299

Gough, Sheryl M; Slape, Christopher I; Aplan, Peter D

2011-09-26

93

In vitro differentiation of B cells and myeloid cells from the early mouse embryo and its extraembryonic yolk sac.  

PubMed

The yolk sac is the first site of hematopoiesis during ontogeny. However, the source of early embryonic hematopoietic stem cells remains unresolved. Early studies have shown that cells obtained from day-8 and -9 extraembryonic yolk sacs can give rise to T cells and myeloid cells, whereas the embryo itself appears to lack such cells. Controversy remains as to whether it is the embryo itself or the extraembryonic yolk sac that contains the initial precursors capable of differentiating into B cells. This study used the approach of enriching hematopoietic stem cells by immunocytoadherence and studying cells isolated from within the embryo itself or from the yolk sac obtained at days 8 and 9 of mouse embryonic development. We report that on day 9, both yolk sac-derived and embryo-derived cells can give rise to B cells and myeloid cells in vitro. On day 8, however, cells isolated from the yolk sac but not from the embryo produce myeloid colonies in vitro; neither source of stem cells generates B cells. Our study suggests that myeloid precursors migrate from yolk sac to embryo earlier than has previously been reported but that the origin for B cell precursors remains to be determined. PMID:8282055

Huang, H; Zettergren, L D; Auerbach, R

1994-01-01

94

Human CD34-derived myeloid dendritic cell development requires intact phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin signaling  

Microsoft Academic Search

Dendritic cells (DCs) are composed of different subsets that exhibit distinct functionality in the induction and regulation of immune\\u000aresponses. The myeloid DC subsets, including interstitial DCs and Langerhans cells (LCs), develop from CD34+ hematopoietic\\u000aprogenitors via direct DC precursors or monocytes. The molecular mechanisms regulating DC development are still largely unknown\\u000aand mostly studied in mice. Phosphatidylinositol 3-kinase (PI3K)

L. van de Laar; M. Buitenhuis; F. M. Wensveen; H. L. A. Janssen; P. J. Coffer; A. M. Woltman

2010-01-01

95

Ectopic TAL-1/SCL expression in phenotypically normal or leukemic myeloid precursors: proliferative and antiapoptotic effects coupled with a differentiation blockade.  

PubMed Central

The TAL-1 gene specifies a basic helix-loop-helix domain (bHLH) transcription factor, which heterodimerizes with E2A gene family proteins. tal-1 protein is abnormally expressed in the majority of T-cell acute lymphoblastic leukemias (T-ALLs). tal-1 is expressed and plays a significant role in normal erythropoietic differentiation and maturation, while its expression in early myeloid differentiation is abruptly shut off at the level of late progenitors/early differentiated precursors (G. L. Condorelli, L. Vitelli, M. Valtieri, I. Marta, E. Montesoro, V. Lulli, R. Baer, and C. Peschle, Blood 86:164-175, 1995). We show that in late myeloid progenitors (the phenotypically normal murine 32D cell line) and early leukemic precursors (the human HL-60 promyelocytic leukemia cell line) ectopic tal-1 expression induces (i) a proliferative effect under suboptimal culture conditions (i.e., low growth factor and serum concentrations respectively), via an antiapoptotic effect in 32D cells or increased DNA synthesis in HL-60 cells, and (ii) a total or marked inhibitory effect on differentiation, respectively, on granulocyte colony-stimulating factor-induced granulopoiesis in 32D cells or retinoic acid- and vitamin D3-induced granulo- and monocytopoiesis in HL-60 cells. Furthermore, experiments with 32D temperature-sensitive p53 cells indicate that aberrant tal-1 expression at the permissive temperature does not exert a proliferative effect but causes p53-mediated apoptosis, i.e., the tal-1 proliferative effect depends on the integrity of the cell cycle checkpoints of the host cell, as observed for c-myc and other oncogenes. tal-1 mutant experiments indicate that ectopic tal-1 effects are mediated by both the DNA-binding and the heterodimerization domains, while the N-terminally truncated tal-1 variant (M3) expressed in T-ALL malignant cells mimics the effects of the wild-type protein. Altogether, our results (i) indicate proliferative and antidifferentiative effects of ectopic tal-1 expression, (ii) shed light on the underlying mechanisms (i.e., requirement for the integrity of the tal-1 bHLH domain and cell cycle checkpoints in the host cell, particularly p53), and (iii) provide new experimental models to further investigate these mechanisms.

Condorelli, G L; Tocci, A; Botta, R; Facchiano, F; Testa, U; Vitelli, L; Valtieri, M; Croce, C M; Peschle, C

1997-01-01

96

Cell cycle control in acute myeloid leukemia  

PubMed Central

Acute myeloid leukemia (AML) is the result of a multistep transforming process of hematopoietic precursor cells (HPCs) which enables them to proceed through limitless numbers of cell cycles and to become resistant to cell death. Increased proliferation renders these cells vulnerable to acquiring mutations and may favor leukemic transformation. Here, we review how deregulated cell cycle control contributes to increased proliferation in AML and favors genomic instability, a prerequisite to confer selective advantages to particular clones in order to adapt and independently proliferate in the presence of a changing microenvironment. We discuss the connection between differentiation and proliferation with regard to leukemogenesis and outline the impact of specific alterations on response to therapy. Finally, we present examples, how a better understanding of cell cycle regulation and deregulation has already led to new promising therapeutic strategies.

Schnerch, Dominik; Yalcintepe, Jasmin; Schmidts, Andrea; Becker, Heiko; Follo, Marie; Engelhardt, Monika; Wasch, Ralph

2012-01-01

97

A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment  

PubMed Central

Somatic Nucleophosmin (NPM1) mutation frequently occurs in acute myeloid leukemia (AML), but its role in leukemogenesis remains unclear. This study reports the first “conventional” knock-in mouse model of Npm1 mutation, which was achieved by inserting TCTG after nucleotide c.857 (c.854_857dupTCTG) to mimic human mutation without any “humanized” sequence. The resultant mutant peptide differed slightly different from that in humans but exhibited cytoplasmic pulling force. Homozygous (Npm1c+/c+) mice showed embryonic lethality before day E8.5, wheras heterozygous (Npm1wt/c+) mice appeared healthy at birth and were fertile. Approximately 36% of Npm1wt/c+ mice developed myeloproliferative disease (MPD) with extramedullary hematopoiesis. Those Npm1wt/c+ mice that did not develop MPD nevertheless gradually developed monocytosis and showed increased numbers of marrow myeloid precursors. This second group of Npm1wt/c+ mice also showed compromised cobblestone area formation, suggesting pathology in the hematopoietic niche. Microarray experiments and bioinformatic analysis on mice myeloid precursor cells and 227 human samples revealed the expression of CXCR4/CXCL12-related genes was significantly suppressed in mutant cells from both mice and humans. Thus, our mouse model demonstrated that Npm1 mutation can result in MPD, but is insufficient for leukemogenesis. Perturbation of hematopoietic niche in mutant hematopoietic stem cells (implied by underrepresentation of CXCR4/CXCL12-related genes) may be important in the pathogenesis of NPM1 mutations.

Chiou, Ji-Shain; Hsu, Yueh-Chwen; Tsai, Mong-Hsun; Chiu, Yu-Chiao; Yu, I-Shing; Lin, Shu-Wha; Hou, Hsin-An; Kuo, Yi-Yi; Lin, Hsiu-Mei; Wu, Ming-Fang; Chou, Wen-Chien; Tien, Hwei-Fang

2012-01-01

98

Clonal analysis of hematopoietic progenitor cells in the zebrafish  

PubMed Central

Identification of hematopoietic progenitor cells in the zebrafish (Danio rerio) has been hindered by a lack of functional assays to gauge proliferative potential and differentiation capacity. To investigate the nature of myeloerythroid progenitor cells, we developed clonal methylcellulose assays by using recombinant zebrafish erythropoietin and granulocyte colony-stimulating factor. From adult whole kidney marrow, erythropoietin was required to support erythroid colony formation, and granulocyte colony-stimulating factor was required to support the formation of colonies containing neutrophils, monocytes, and macrophages. Myeloid and erythroid colonies showed distinct morphologies and were easily visualized and scored by their expression of lineage-specific fluorescent transgenes. Analysis of the gene-expression profiles after isolation of colonies marked by gata1:DsRed or mpx:eGFP transgenes confirmed our morphological erythroid and myeloid lineage designations, respectively. The majority of progenitor activity was contained within the precursor light scatter fraction, and more immature precursors were present within the lymphoid fraction. Finally, we performed kinetic analyses of progenitor activity after sublethal irradiation and demonstrated that recovery to preirradiation levels occurred by 14 days after irradiation. Together, these experiments provide the first report of clonal hematopoietic progenitor assays in the zebrafish and establish the number, characteristics, and kinetics of myeloerythroid progenitors during both steady-state and stress hematopoiesis.

Stachura, David L.; Svoboda, Ondrej; Lau, Ryan P.; Balla, Keir M.; Zon, Leonard I.; Bartunek, Petr

2011-01-01

99

Absence of the transcription factor CCAAT enhancer binding protein ? results in loss of myeloid identity in bcr/abl-induced malignancy  

PubMed Central

The lineage-determining transcription factor CCAAT enhancer binding protein ? (C/EBP?) is required for myeloid differentiation. Decreased function or expression of C/EBP? is often found in human acute myeloid leukemia. However, the precise impact of C/EBP? deficiency on the maturation arrest in leukemogenesis is not well understood. To address this question, we used a murine transplantation model of a bcr/abl-induced myeloproliferative disease. The expression of bcr/abl in C/EBP?pos fetal liver cells led to a chronic myeloid leukemia-like disease. Surprisingly, bcr/abl-expressing C/EBP??/? fetal liver cells failed to induce a myeloid disease in transplanted mice, but caused a fatal, transplantable erythroleukemia instead. Accordingly, increased expression of the transcription factors SCL and GATA-1 in hematopoietic precursor cells of C/EBP??/? fetal livers was found. The mechanism for the lineage shift from myeloid to erythroid leukemia was studied in a bcr/abl-positive cell line. Consistent with findings of the transplant model, expression of C/EBP? and GATA-1 was inversely correlated. Id1, an inhibitor of erythroid differentiation, was identified as a critical direct target of C/EBP?. Down-regulation of Id1 by RNA interference impaired C/EBP?-induced granulocytic differentiation. Taken together, our study provides evidence that myeloid lineage identity of malignant hematopoietic progenitor cells requires the residual expression of C/EBP?.

Wagner, Katharina; Zhang, Pu; Rosenbauer, Frank; Drescher, Bettina; Kobayashi, Susumu; Radomska, Hanna S.; Kutok, Jeffery L.; Gilliland, D. Gary; Krauter, Jurgen; Tenen, Daniel G.

2006-01-01

100

Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemia-associated antigens: implications for the graft-versus-leukemia effect and peptide vaccine-based immunotherapy  

Microsoft Academic Search

The cure of chronic myeloid leukemia (CML) patients following allogeneic stem cell transplantation (SCT) is attributed to graft-versus-leukemia (GVL) effects targeting alloantigens and\\/or leukemia-associated antigens (LAA) on leukemia cells. To assess the potential of LAA-peptide vaccines in eliminating leukemia in CML patients, we measured WT1, PR3, ELA2 and PRAME expression in CD34+ progenitor subpopulations in CML patients and compared them

A S M Yong; K Keyvanfar; R Eniafe; B N Savani; K Rezvani; E M Sloand; J M Goldman; A J Barrett; ASM Yong

2008-01-01

101

Alcohol Impairs the Myeloid Proliferative Response to Bacteremia in Mice via Inhibiting the Stem Cell Antigen-1 - Extracellular-Regulated Kinase Pathway1  

PubMed Central

Enhancement of stem cell antigen-1 (Sca-1) expression by myeloid precursors promotes the granulopoietic response to bacterial infection. However, the underlying mechanisms remain unclear. Extracellular-regulated kinase (ERK) pathway activation strongly enhances proliferation of hematopoietic progenitor cells. Here, we investigated the role of Sca-1 in promoting ERK-dependent myeloid lineage proliferation and the effects of alcohol on this process. Thirty minutes after intraperitoneal injection of alcohol, mice received intravenous challenge with 5 × 107 E.coli for 8 or 24 h. A subset of mice received intravenous BrdU injection 20 h post challenge. Bacteremia increased Sca-1 expression, ERK activation, and proliferation of myeloid and granulopoietic precursors. Alcohol administration suppressed this response and impaired granulocyte production. Sca-1 expression positively correlated with ERK activation and cell cycling, but negatively correlated with myeloperoxidase content in granulopoietic precursors. Alcohol intoxication suppressed ERK activation in granulopoietic precursors and proliferation of these cells during bacteremia. Granulopoietic precursors in Sca-1?/? mice failed to activate ERK signaling and could not increase CFU-GM activity following bacteremia. These data indicate that Sca-1 expression promotes ERK-dependent myeloid cell proliferation during bacteremia. Suppression of this response could represent an underlying mechanism for developing myelosuppression in alcohol abusing hosts with severe bacterial infection.

Melvan, John Nicholas; Siggins, Robert W.; Stanford, William L.; Porretta, Connie; Nelson, Steve; Bagby, Gregory J.; Zhang, Ping

2011-01-01

102

Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis.  

PubMed

One of the pathological hallmarks of Alzheimer disease is the accumulation of amyloid plaques in the extracellular space in the brain. Amyloid plaques are primarily composed of aggregated amyloid ? peptide (A?), a proteolytic fragment of the transmembrane amyloid precursor protein (APP). For APP to be proteolytically cleaved into A?, it must be internalized into the cell and trafficked to endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs) in the phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) gene were significantly associated with Alzheimer disease, suggesting a role in APP endocytosis and A? generation. Here, we show that PICALM co-localizes with APP in intracellular vesicles of N2a-APP cells after endocytosis is initiated. PICALM knockdown resulted in reduced APP internalization and A? generation. Conversely, PICALM overexpression increased APP internalization and A? production. In vivo, PICALM was found to be expressed in neurons and co-localized with APP throughout the cortex and hippocampus in APP/PS1 mice. PICALM expression was altered using AAV8 gene transfer of PICALM shRNA or PICALM cDNA into the hippocampus of 6-month-old APP/PS1 mice. PICALM knockdown decreased soluble and insoluble A? levels and amyloid plaque load in the hippocampus. Conversely, PICALM overexpression increased A? levels and amyloid plaque load. These data indicate that PICALM, an adaptor protein involved in clathrin-mediated endocytosis, regulates APP internalization and subsequent A? generation. PICALM contributes to amyloid plaque load in brain likely via its effect on A? metabolism. PMID:22539346

Xiao, Qingli; Gil, So-Chon; Yan, Ping; Wang, Yan; Han, Sharon; Gonzales, Ernie; Perez, Ronaldo; Cirrito, John R; Lee, Jin-Moo

2012-04-26

103

Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis*  

PubMed Central

One of the pathological hallmarks of Alzheimer disease is the accumulation of amyloid plaques in the extracellular space in the brain. Amyloid plaques are primarily composed of aggregated amyloid ? peptide (A?), a proteolytic fragment of the transmembrane amyloid precursor protein (APP). For APP to be proteolytically cleaved into A?, it must be internalized into the cell and trafficked to endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs) in the phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) gene were significantly associated with Alzheimer disease, suggesting a role in APP endocytosis and A? generation. Here, we show that PICALM co-localizes with APP in intracellular vesicles of N2a-APP cells after endocytosis is initiated. PICALM knockdown resulted in reduced APP internalization and A? generation. Conversely, PICALM overexpression increased APP internalization and A? production. In vivo, PICALM was found to be expressed in neurons and co-localized with APP throughout the cortex and hippocampus in APP/PS1 mice. PICALM expression was altered using AAV8 gene transfer of PICALM shRNA or PICALM cDNA into the hippocampus of 6-month-old APP/PS1 mice. PICALM knockdown decreased soluble and insoluble A? levels and amyloid plaque load in the hippocampus. Conversely, PICALM overexpression increased A? levels and amyloid plaque load. These data indicate that PICALM, an adaptor protein involved in clathrin-mediated endocytosis, regulates APP internalization and subsequent A? generation. PICALM contributes to amyloid plaque load in brain likely via its effect on A? metabolism.

Xiao, Qingli; Gil, So-Chon; Yan, Ping; Wang, Yan; Han, Sharon; Gonzales, Ernie; Perez, Ronaldo; Cirrito, John R.; Lee, Jin-Moo

2012-01-01

104

Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study  

PubMed Central

Objective We conducted a prospective, randomized, open-label, multicenter study to compare busulfan plus fludarabine (BuFlu) with busulfan plus cyclophosphamide (BuCy) as the conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) in first complete remission (CR1). Methods Totally 108 AML-CR1 patients undergoing allo-HSCT were randomized into BuCy (busulfan 1.6 mg/kg, q12 hours, -7?~?-4d; cyclophosphamide 60 mg/kg.d, -3?~?-2d) or BuFlu (busulfan 1.6 mg/kg, q12 hours, -5?~?-2d; fludarabine 30 mg/m2.d, -6?~?-2d) group. Hematopoietic engraftment, regimen-related toxicity (RRT), graft-versus-host disease (GVHD), transplant related mortality (TRM), and overall survival were compared between the two groups. Results All patients achieved hematopoietic reconstitution except for two patients who died of RRT during conditioning. All patients obtained complete donor chimerism by day +30 post-transplantation. The incidence of total and III-IV RRT were 94.4% and 81.5% (P?=?0.038), and 16.7% and 0.0% (P?=?0.002), respectively, in BuCy and BuFlu group. With a median follow up of 609 (range, 3–2130) days after transplantation, the 5-year cumulative incidence of TRM were 18.8?±?6.9% and 9.9?±?6.3% (P?=?0.104); the 5-year cumulative incidence of leukemia relapse were 16.5?±?5.8% and 16.2?±?5.3% (P?=?0.943); the 5-year disease-free survival and overall survival were 67.4?±?7.6% and 75.3?±?7.2% (P = 0.315), and 72.3?±?7.5% and 81.9?±?7.0% (P?=?0.177), respectively in BuCy and BuFlu group. Conclusion Compared with BuCy, BuFlu as a myeloablative condition regimen was associated with lower toxicities and comparable anti-leukemic activity in AML-CR1 patients undergoing allo-HSCT.

2013-01-01

105

Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group.  

PubMed

A total of 155 patients with acute myeloid leukemia (AML) received hematopoietic stem cell transplants from unrelated donors after standard conditioning. Clinical outcome after the use of two different antithymocyte globulins for the prevention of graft-versus-host disease (GvHD) was analyzed in a retrospective study as follows: rabbit ATG (Thymoglobulin Sangstat/Genzyme, n=49, median age 42 years, 53% in CR, further ATG-S); rabbit ATG (ATG-Fresenius, n=38, median age 42 years, 58% in CR, further ATG-F) or no ATG (n=68, median age 36 years, 55% in CR). The groups were comparable regarding disease status at transplant, age, CMV status and cytogenetics. Grade III-IV acute GvHD was found in 15% in the ATG and 27% in the no ATG group (P=0.44). The most important independent risk factors for chronic GvHD (cGvHD) were the use of ATG, disease status at transplant and conditioning. cGvHD developed significantly more frequently in no ATG group. With the median follow-up of 34 months, the 5-year survival is 42% for those transplanted in CR. To conclude, these data demonstrate that the transplants performed in CR, with ATG, are associated with a good outcome, low incidence of cGvHD and no increase of relapse. PMID:15821768

Basara, N; Baurmann, H; Kolbe, K; Yaman, A; Labopin, M; Burchardt, A; Huber, C; Fauser, A A; Schwerdtfeger, R

2005-05-01

106

Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV.  

PubMed

The role of allogeneic stem cell transplantation in chronic myeloid leukemia is being reevaluated. Whereas drug treatment has been shown to be superior in first-line treatment, data on allogeneic hematopoietic stem cell transplantation (allo SCT) as second-line therapy after imatinib failure are scarce. Using an interim safety analysis of the randomized German CML Study IV designed to optimize imatinib therapy by combination, dose escalation, and transplantation, we here report on 84 patients who underwent consecutive transplantation according to predefined criteria (low European Group for Blood and Marrow Transplantation [EBMT] score, imatinib failure, and advanced disease). Three-year survival after transplantation of 56 patients in chronic phase was 91% (median follow-up: 30 months). Transplantation-related mortality was 8%. In a matched pair comparison of patients who received a transplant and those who did not, survival was not different. Three-year survival after transplantation of 28 patients in advanced phase was 59%. Eighty-eight percent of patients who received a transplant achieved complete molecular remissions. We conclude that allo SCT could become the preferred second-line option after imatinib failure for suitable patients with a donor. The study is registered at the National Institutes of Health, http://clinicaltrials.gov: NCT00055874. PMID:19965667

Saussele, Susanne; Lauseker, Michael; Gratwohl, Alois; Beelen, Dietrich W; Bunjes, Donald; Schwerdtfeger, Rainer; Kolb, Hans-Jochem; Ho, Anthony D; Falge, Christiane; Holler, Ernst; Schlimok, Günter; Zander, Axel R; Arnold, Renate; Kanz, Lothar; Dengler, Robert; Haferlach, Claudia; Schlegelberger, Brigitte; Pfirrmann, Markus; Müller, Martin C; Schnittger, Susanne; Leitner, Armin; Pletsch, Nadine; Hochhaus, Andreas; Hasford, Joerg; Hehlmann, Rüdiger

2009-11-18

107

Development and homeostasis of "resident" myeloid cells: the case of the microglia.  

PubMed

Microglia, macrophages of the central nervous system, play an important role in brain homeostasis. Their origin has been unclear. Recent fate-mapping experiments have established that microglia mostly originate from Myb-independent, FLT3-independent, but PU.1-dependent precursors that express the CSF1-receptor at E8.5 of embryonic development. These precursors are presumably located in the yolk sac (YS) at this time before invading the embryo between E9.5 and E10.5 and colonizing the fetal liver. Indeed, the E14.5 fetal liver contains a large population of Myb-independent YS-derived myeloid cells. This myeloid lineage is distinct from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development and maintenance. This "yolky" beginning and the independence from conventional HSCs are not unique to microglia. Indeed, several other populations of F4/80-positive macrophages develop also from YS Myb-independent precursors, such as Kupffer cells in the liver, Langerhans cells in the epidermis, and macrophages in the spleen, kidney, pancreas, and lung. Importantly, microglia and the other Myb-independent macrophages persist, at least in part, in adult mice and likely self-renew within their respective tissues of residence, independently of bone marrow HSCs. This suggests the existence of tissue resident macrophage "stem cells" within tissues such as the brain, and opens a new era for the molecular and cellular understanding of myeloid cells responses during acute and chronic inflammation. PMID:22847963

Gomez Perdiguero, Elisa; Schulz, Christian; Geissmann, Frederic

2012-07-28

108

Revision of the human hematopoietic tree: granulocyte subtypes derive from distinct hematopoietic lineages.  

PubMed

The classical model of hematopoiesis predicts a dichotomous lineage restriction of multipotent hematopoietic progenitors (MPPs) into common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs). However, this idea has been challenged by the identification of lymphoid progenitors retaining partial myeloid potential (e.g., LMPPs), implying that granulocytes can arise within both the classical lymphoid and the myeloid branches. Here, we resolve this issue by using cell-surface CD133 expression to discriminate functional progenitor populations. We show that eosinophilic and basophilic granulocytes as well as erythrocytes and megakaryocytes derive from a common erythro-myeloid progenitor (EMP), whereas neutrophilic granulocytes arise independently within a lympho-myeloid branch with long-term progenitor function. These findings challenge the concept of a CMP and restore dichotomy to the classical hematopoietic model. PMID:23707063

Görgens, André; Radtke, Stefan; Möllmann, Michael; Cross, Michael; Dürig, Jan; Horn, Peter A; Giebel, Bernd

2013-05-23

109

Myeloid-derived Suppressor Cells Adhere to Physiologic STAT3- vs STAT5-dependent Hematopoietic Programming, Establishing Diverse Tumor-Mediated Mechanisms of Immunologic Escape  

PubMed Central

The receptor tyrosine kinase inhibitor, sunitinib, is astonishingly effective in its capacity to reduce MDSCs in peripheral tissues such as blood (human) and spleen (mouse), restoring responsiveness of bystander T lymphocytes to TcR stimulation. Sunitinib blocks proliferation of undifferentiated MDSCs and decreases survival of more differentiated neutrophilic MDSC (n-MDSC) progeny. Ironically, sunitinib’s profound effects are observed even in a total absence of detectable anti-tumor therapeutic response. This is best explained by the presence of disparate MDSC-conditioning stimuli within individual body compartments, allowing sensitivity and resistance to sunitinib to coexist within the same mouse or patient. The presence or absence of GM-CSF is likely the major determinant in each compartment, given that GM-CSF’s capacity to preempt STAT3-dependent with dominant STAT5-dependent hematopoietic programming confers sunitinib resistance and redirects differentiation from the n-MDSC lineage to the more versatile monocytoid (m-MDSC) lineage. The clinical sunitinib experience underscores that strategies for MDSC and Treg depletions must be mindful of disparities among body compartments to avoid sanctuary effects. Ironically, m-MDSCs manifesting resistance to sunitinib also have the greatest potential to differentiate into tumoricidal accessory cells, by virtue of their capacity to respond to T cell-secreted IFN-? or to TLR agonists with nitric oxide and peroxynitrate production.

Cohen, Peter A.; Ko, Jennifer S.; Storkus, Walter J.; Spencer, Christopher D.; Bradley, Judy M.; Gorman, Jessica E.; McCurry, Dustin B.; Zorro-Manrique, Soroya; Dominguez, Anna Lucia; Pathangey, Latha B.; Rayman, Patricia A.; Rini, Brian I.; Gendler, Sandra J.; Finke, James H.

2013-01-01

110

Myeloid Translocation Gene 16 (MTG16) Interacts with Notch Transcription Complex Components To Integrate Notch Signaling in Hematopoietic Cell Fate Specification? †  

PubMed Central

The Notch signaling pathway regulates gene expression programs to influence the specification of cell fate in diverse tissues. In response to ligand binding, the intracellular domain of the Notch receptor is cleaved by the ?-secretase complex and then translocates to the nucleus. There, it binds the transcriptional repressor CSL, triggering its conversion to an activator of Notch target gene expression. The events that control this conversion are poorly understood. We show that the transcriptional corepressor, MTG16, interacts with both CSL and the intracellular domains of Notch receptors, suggesting a pivotal role in regulation of the Notch transcription complex. The Notch1 intracellular domain disrupts the MTG16-CSL interaction. Ex vivo fate specification in response to Notch signal activation is impaired in Mtg16?/? hematopoietic progenitors, and restored by MTG16 expression. An MTG16 derivative lacking the binding site for the intracellular domain of Notch1 fails to restore Notch-dependent cell fate. These data suggest that MTG16 interfaces with critical components of the Notch transcription complex to affect Notch-dependent lineage allocation in hematopoiesis.

Engel, Michael E.; Nguyen, Hong N.; Mariotti, Jolene; Hunt, Aubrey; Hiebert, Scott W.

2010-01-01

111

Comparative Outcomes of Donor Graft CD34+ Selection and Immune Suppressive Therapy As Graft-Versus-Host Disease Prophylaxis for Patients With Acute Myeloid Leukemia in Complete Remission Undergoing HLA-Matched Sibling Allogeneic Hematopoietic Cell Transplantation  

PubMed Central

Purpose T-cell depletion (TCD) reduces the incidence of graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT). However, concerns about relapse, graft rejection, and variability in technique have limited the widespread application of this approach. Patients and Methods Outcomes of 44 patients receiving HLA-identical sibling TCD grafts using a uniform technique for CD34+ selection as the sole form of immune suppression were compared with outcomes of 84 patients receiving T-replete grafts and pharmacologic immune suppression therapy (IST). Results Groups were similar, except for fewer men (36% with TCD v 56% with IST) and more frequent use of radiation-containing regimens (100% with TCD v 50% with IST) in the CD34-selected TCD cohort. The proportion of patients with neutrophil engraftment at day 28 was similar (96% with IST and 100% with TCD grafts). The 100-day rates of grade 2 to 4 acute GVHD were 39% and 23% with IST and TCD grafts, respectively (P = .07). Corresponding 2-year rates of chronic GVHD were lower with TCD grafts than IST (19% v 50%, respectively; P < .001). There were no differences in rates of graft rejection, leukemia relapse, treatment-related mortality, and disease-free and overall survival rates. At 1 year, 54% and 12% of patients were still on immunosuppression in the IST and TCD cohorts, respectively. TCD was associated with a higher GVHD-free survival at 2 years compared with IST (41% v 19%, respectively; P = .006). Conclusion These results suggest that TCD via CD34 selection might lower long-term morbidity as a result of chronic GVHD without negatively impacting relapse rates in patients with acute myeloid leukemia. Additional prospective studies should be undertaken to definitively address the role of TCD in HCT.

Pasquini, Marcelo C.; Devine, Steven; Mendizabal, Adam; Baden, Lindsey R.; Wingard, John R.; Lazarus, Hillard M.; Appelbaum, Frederick R.; Keever-Taylor, Carolyn A.; Horowitz, Mary M.; Carter, Shelly; O'Reilly, Richard J.; Soiffer, Robert J.

2012-01-01

112

Intra-hematopoietic cell fusion as a source of somatic variation in the hematopoietic system  

PubMed Central

Summary Cell fusion plays a well-recognized, physiological role during development. Bone-marrow-derived hematopoietic cells have been shown to fuse with non-hematopoietic cells in a wide variety of tissues. Some organs appear to resolve the changes in ploidy status, generating functional and mitotically-competent events. However, cell fusion exclusively involving hematopoietic cells has not been reported. Indeed, genomic copy number variation in highly replicative hematopoietic cells is widely considered a hallmark of malignant transformation. Here we show that cell fusion occurs between cells of the hematopoietic system under injury as well as non-injury conditions. Experiments reveal the acquisition of genetic markers in fusion products, their tractable maintenance during hematopoietic differentiation and long-term persistence after serial transplantation. Fusion events were identified in clonogenic progenitors as well as differentiated myeloid and lymphoid cells. These observations provide a new experimental model for the study of non-pathogenic somatic diversity in the hematopoietic system.

Skinner, Amy M.; Grompe, Markus; Kurre, Peter

2012-01-01

113

Hematopoietic stem cell-based gene therapy for acquired immunodeficiency syndrome: efficient transduction and expression of RevM10 in myeloid cells in vivo and in vitro.  

PubMed

Gene delivery via the hematopoietic stem cell (HSC) offers an attractive means to introduce antiviral genes into both T cells and macrophages for acquired immunodeficiency syndrome (AIDS) gene therapy. An amphotropic retroviral vector encoding a bicistronic gene coexpressing RevM10 and the murine CD8alpha' chain (lyt2) was developed to transduce HSC/progenitor cells. After transduction of CD34+ cells isolated from human umbilical cord blood, the lyt2 molecule detected by flow cytometry was used to monitor the level of gene transduction and expression and to enrich RevM10-expressing cells by cell sorting without drug selection. Using this quantitative method, high levels of gene transduction and expression (around 20%) were achieved by high-speed centrifugation of CD34+ cells with the retroviral supernatant (spinoculation). After reconstitution of human bone marrow implanted in SCID mice (SCID-hu bone) with the transduced HSC/progenitor cells, a significant number of donor-derived CD14+ bone marrow cells were found to express the RevM10/lyt2 gene. Finally, replication of a macrophage-tropic human immunodeficiency virus-type 1 (HIV-1) isolate was greatly inhibited in the lyt2+/CD14+ cells differentiated from transduced CD34+ cells after the enrichment of lyt2+ population. Thus, the RevM10 gene did not appear to inhibit the differentiation of HSC/progneitor cells into monocytes/macrophages. The level of retrovirus-mediated RevM10 expression in monocytes/macrophages derived from transduced HSCs is sufficient to suppress HIV-1 replication. PMID:9116270

Su, L; Lee, R; Bonyhadi, M; Matsuzaki, H; Forestell, S; Escaich, S; Böhnlein, E; Kaneshima, H

1997-04-01

114

Signal transduction pathways that contribute to myeloid differentiation  

Microsoft Academic Search

The production of mature, differentiated myeloid cells is regulated by the action of hematopoietic cytokines on progenitor cells in the bone marrow. Cytokines drive the process of myeloid differentiation by binding to specific cell-surface receptors in a stage- and lineage-specific manner. Following the binding of a cytokine to its cognate receptor, intracellular signal-transduction pathways become activated that facilitate the myeloid

M B Miranda; D E Johnson

2007-01-01

115

Defining incidence, risk factors, and impact on survival of central line-associated blood stream infections following hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome.  

PubMed

Central line-associated blood stream infections (CLABSI) commonly complicate the care of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic stem cell transplantation (HCT). We developed a modified CLABSI (MCLABSI) definition that attempts to exclude pathogens usually acquired because of disruption of mucosal barriers during the vulnerable neutropenic period following HCT that are generally included under the original definition (OCLABSI). We conducted a retrospective study of all AML and MDS patients undergoing HCT between August 2009 and December 2011 at the Cleveland Clinic (N = 73), identifying both OCLABSI and MCLABSI incidence. The median age at transplantation was 52 years (range, 16 to 70); 34 had a high (?3) HCT comorbidity index (HCT-CI); 34 received bone marrow (BM), 24 received peripheral stem cells (PSC), and 15 received umbilical cord blood cells (UCB). Among these 73 patients, 23 (31.5%) developed OCLABSI, of whom 16 (69.6%) died, and 8 (11%) developed MCLABSI, of whom 7 (87.5%) died. OCLABSI was diagnosed a median of 9 days from HCT: 5 days (range, 2 to 12) for UCB and 78 days (range, 7 to 211) for BM/PSC (P < .001). MCLABSI occurred a median of 12 days from HCT, with similar earlier UCB and later BM/PSC diagnosis (P = .030). Risk factors for OCLABSI in univariate analysis included CBC (P < .001), human leukocyte antigen (HLA)-mismatch (P = .005), low CD34(+) count (P = .007), low total nucleated cell dose (P = .016), and non-Caucasian race (P = .017). Risk factors for OCLABSI in multivariable analysis were UCB (P < .001) and high HCT-CI (P = .002). There was a significant increase in mortality for both OCLABSI (hazard ratio, 7.14; CI, 3.31 to 15.37; P < .001) and MCLABSI (hazard ratio, 6.44; CI, 2.28 to 18.18; P < .001). CLABSI is common and associated with high mortality in AML and MDS patients undergoing HCT, especially in UCB recipients and those with high HCT-CI. We propose the MCLABSI definition to replace the OCLABSI definition, given its greater precision for identifying preventable infection in HCT patients. PMID:23380342

Lukenbill, Joshua; Rybicki, Lisa; Sekeres, Mikkael A; Zaman, Muhammad Omer; Copelan, Alexander; Haddad, Housam; Fraser, Thomas; DiGiorgio, Megan J; Hanna, Rabi; Duong, Hien; Hill, Brian; Kalaycio, Matt; Sobecks, Ronald; Bolwell, Brian; Copelan, Edward

2013-02-01

116

Sinister Symbiosis: Pathological Hematopoietic-Stromal Interactions in CML.  

PubMed

The impact of myeloid malignancies on the nonhematopoietic components of the bone marrow remains poorly understood. In this issue of Cell Stem Cell, Schepers et al. (2013) describe how malignant myeloid cells alter the endosteal hematopoietic stem cell (HSC) niche, resulting in the expansion of osteoblastic lineage cells that preferentially support malignant HSCs. PMID:24012363

Mullally, Ann; Ebert, Benjamin L

2013-09-01

117

JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFN?.  

PubMed

The acquired gain-of-function V617F mutation in the Janus Kinase 2 (JAK2(V617F)) is the main mutation involved in BCR/ABL-negative myeloproliferative neoplasms (MPNs), but its effect on hematopoietic stem cells as a driver of disease emergence has been questioned. Therefore, we reinvestigated the role of endogenous expression of JAK2(V617F) on early steps of hematopoiesis as well as the effect of interferon-? (IFN?), which may target the JAK2(V617F) clone in humans by using knock-in mice with conditional expression of JAK2(V617F) in hematopoietic cells. These mice develop a MPN mimicking polycythemia vera with large amplification of myeloid mature and precursor cells, displaying erythroid endogenous growth and progressing to myelofibrosis. Interestingly, early hematopoietic compartments [Lin-, LSK, and SLAM (LSK/CD48-/CD150+)] increased with the age. Competitive repopulation assays demonstrated disease appearance and progressive overgrowth of myeloid, Lin-, LSK, and SLAM cells, but not lymphocytes, from a low number of engrafted JAK2(V617F) SLAM cells. Finally, IFN? treatment prevented disease development by specifically inhibiting JAK2(V617F) cells at an early stage of differentiation and eradicating disease-initiating cells. This study shows that JAK2(V617F) in mice amplifies not only late but also early hematopoietic cells, giving them a proliferative advantage through high cell cycling and low apoptosis that may sustain MPN emergence but is lost upon IFN? treatment. PMID:23863895

Hasan, Salma; Lacout, Catherine; Marty, Caroline; Cuingnet, Marie; Solary, Eric; Vainchenker, William; Villeval, Jean-Luc

2013-07-17

118

Karyotyping, immunophenotyping, and apoptosis analyses on human hematopoietic precursor cells derived from umbilical cord blood following long-term ex vivo expansion  

Microsoft Academic Search

By means of flow cytometry, CD34+\\/CD38? hematopoietic stem cells (HSC) were collected from umbilical cord blood (UCB) of 10 healthy women at the time of delivery and cultivated in stem-cell culture media supplemented with cell growth stimulating factors (IL-3, IL-6, GM-CSF, EPO, IGF-1, and SCF) for long periods. Apoptotic status, cell surface marker expression, and karyotypes of the cultured UCB-derived

Hong Tian; Shiang Huang; Feili Gong; Lei Tian; Zhong Chen

2005-01-01

119

Hematopoietic progenitor cell collection.  

PubMed

Hematopoietic progenitor cells can be mobilized from the bone marrow microenvironment into the peripheral blood following treatment of patients with myeloid cytokines (GCSF, GMCSF, IL3), a CXCR4 antagonist (Plerixafor) and/or following a hematopoietic recovery from cytotoxic chemotherapy. The hematopoietic stem and progenitor cells are contained within the mononuclear cell fraction of peripheral blood and can be collected by apheresis in which the cellular constituents of the blood are separated on the basis of their buoyant density. Modern apheresis allows processing of five or more blood volumes (24 L or more) over a 4-5-h period to efficiently remove and separate more than 70 % of the CD34 positive cell progenitors present to blood. Management of a patient undergoing apheresis requires careful attention to venous access, calcium placement to counteract the effects of the citrate uses anticoagulant and hemodynamic monitoring. The principles of setting up the COBE spectra and its operation are reviewed. Management of common toxicities including hypocalcemia, allergic reactions, and vasovagal reactions are described in the next chapter. PMID:22890924

Marlow, S Darlene; House, Myra

2012-01-01

120

Coordinate regulation of HOX genes in human hematopoietic cells.  

PubMed Central

Hematopoiesis is a continuous process in which precursor cells proliferate and differentiate throughout life. However, the molecular mechanisms that govern this process are not clearly defined. Homeobox-containing genes, encoding DNA-binding homeodomains, are a network of genes highly conserved throughout evolution. They are organized in clusters expressed in the developing embryo with a positional hierarchy. We have analyzed expression of the four human HOX loci in erythroleukemic, promyelocytic, and monocytic cell lines to investigate whether the physical organization of human HOX genes reflects a regulatory hierarchy involved in the differentiation process of hematopoietic cells. Our results demonstrate that cells representing various stages of hematopoietic differentiation display differential patterns of HOX gene expression and that HOX genes are coordinately switched on or off in blocks that may include entire loci. The entire HOX4 locus is silent in all lines analyzed and almost all the HOX2 genes are active in erythroleukemic cells and turned off in myeloid-restricted cells. Our observations provide information about the regulation of HOX genes and suggest that the coordinate regulation of these genes may play an important role in lineage determination during early steps of hematopoiesis. Images

Magli, M C; Barba, P; Celetti, A; De Vita, G; Cillo, C; Boncinelli, E

1991-01-01

121

Mobilisation of Hematopoietic CD34+ Precursor Cells in Patients with Acute Stroke Is Safe - Results of an Open-Labeled Non Randomized Phase I/II Trial  

PubMed Central

Background Regenerative strategies in the treatment of acute stroke may have great potential. Hematopoietic growth factors mobilize hematopoietic stem cells and may convey neuroprotective effects. We examined the safety, potential functional and structural changes, and CD34+ cell–mobilization characteristics of G-CSF treatment in patients with acute ischemic stroke. Methods and Results Three cohorts of patients (8, 6, and 6 patients per cohort) were treated subcutaneously with 2.5, 5, or 10 µg/kg body weight rhG-CSF for 5 consecutive days within 12 hrs of onset of acute stroke. Standard treatment included IV thrombolysis. Safety monitoring consisted of obtaining standardized clinical assessment scores, monitoring of CD34+ stem cells, blood chemistry, serial neuroradiology, and neuropsychology. Voxel-guided morphometry (VGM) enabled an assessment of changes in the patients' structural parenchyma. 20 patients (mean age 55 yrs) were enrolled in this study, 5 of whom received routine thrombolytic therapy with r-tPA. G-CSF treatment was discontinued in 4 patients because of unrelated adverse events. Mobilization of CD34+ cells was observed with no concomitant changes in blood chemistry, except for an increase in the leukocyte count up to 75,500/µl. Neuroradiological and neuropsychological follow-up studies did not disclose any specific G-CSF toxicity. VGM findings indicated substantial atrophy of related hemispheres, a substantial increase in the CSF space, and a localized increase in parenchyma within the ischemic area in 2 patients. Conclusions We demonstrate a good safety profile for daily administration of G-CSF when begun within 12 hours after onset of ischemic stroke and, in part in combination with routine IV thrombolysis. Additional analyses using VGM and a battery of neuropsychological tests indicated a positive functional and potentially structural effect of G-CSF treatment in some of our patients. Trial Registration German Clinical Trial Register DRKS 00000723

Kraemer, Mathias; Schormann, Thorsten; Schlachetzki, Felix; Schuierer, Gerhard; Luerding, Ralph; Hennemann, Burkhard; Orso, Evelyn; Dabringhaus, Andreas; Winkler, Jurgen; Bogdahn, Ulrich

2011-01-01

122

Parvovirus Infection Suppresses Long-Term Repopulating Hematopoietic Stem Cells  

PubMed Central

The functional disturbance of self-renewing and multipotent hematopoietic stem cells (HSCs) in viral diseases is poorly understood. In this report, we have assessed the susceptibility of mouse HSCs to strain i of the autonomous parvovirus minute virus of mice (MVMi) in vitro and during persistent infection of an immunodeficient host. Purified 5FUr Lin? Sca-1+ primitive hematopoietic precursors were permissive for MVMi genome replication and the expression of viral gene products. The lymphoid and myeloid repopulating capacity of bone marrow (BM) cells was significantly impaired after in vitro infection, although the degree of functional effect proportionally decreased with the posttransplantation time. This indicated that MVMi targets the heterogeneous compartment of repopulating cells with differential affinity and suggests that the virus may persist in some primitive HSCs in the quiescent stage, killing those eventually recruited for proliferative activity. Immunodeficient SCID mice oronasally infected with MVMi were cured of the characteristic virus-induced lethal leukopenia by transplantation of immunocompetent BM grafts. However, two double-stranded viral DNA species, probably uncommon replicative intermediates, remained in the marrow of every transplanted mouse months after infectious virus clearance. Genetic analysis of the rescued mice showed that the infection ensured a stable engraftment of donor hematopoiesis by markedly depleting the pool of endogenous HSCs. The MVMi-induced suppression of HSC functions illustrates the accessibility of this compartment to infection during a natural viral hematological disease. These results may provide clues to understanding delayed hematopoietic syndromes associated with persistent viral infections and to prospective gene delivery to HSCs in vivo.

Segovia, Jose C.; Guenechea, Guillermo; Gallego, Jesus M.; Almendral, Jose M.; Bueren, Juan A.

2003-01-01

123

Expression and Function of PML-RARA in the Hematopoietic Progenitor Cells of Ctsg-PML-RARA Mice  

PubMed Central

Because PML-RARA-induced acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, many groups have speculated about whether its leukemic cell of origin is a committed myeloid precursor (e.g. a promyelocyte) versus an hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg, and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice), are expressed in the purified KLS cells of these mice (KLS?=?Kit+Lin?Sca+, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Further, we demonstrate the transcriptional consequences of PML-RARA expression in Ctsg-PML-RARA mice in early myeloid development in other myeloid progenitor compartments [common myeloid progenitors (CMPs) and granulocyte/monocyte progenitors (GMPs)], which have a distinct gene expression signature compared to wild-type (WT) mice. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice and alters the transcriptional signature of these cells, it does not induce their self-renewal. In sum, these results demonstrate that in the Ctsg-PML-RARA mouse model of APL, PML-RARA is expressed in and affects the function of multipotent progenitor cells. Finally, since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in this mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients.

Uy, Geoffrey L.; Klco, Jeffery M.; Lamprecht, Tamara; Varghese, Nobish; Nagarajan, Rakesh; Ley, Timothy J.

2012-01-01

124

Anti-PrP Mab 6D11 suppresses PrPSc replication in prion infected myeloid precursor line FDC-P1/22L and in the lymphoreticular system in vivo  

PubMed Central

The pathogenesis of prion diseases is related to conformational transformation of cellular prion protein (PrPC) into a toxic, infectious, and self-replicating conformer termed PrPSc. Following extracerebral inoculation, the replication of PrPSc is confined for months to years to the lymporeticular system (LRS) before the secondary CNS involvement results in occurrence of neurological symptoms. Therefore, replication of PrPSc, in the early stage of infection can be targeted by therapeutic approaches, which like passive immunization have limited blood-brain-barrier penetration. In this study, we show that 6D11 anti-PrP monoclonal antibody (Mab) prevents infection on a FDC-P1 myeloid precursor cell line stably infected with 22L mouse adapted scrapie strain. Passive immunization of extracerebrally infected CD-1 mice with Mab 6D11 resulted in effective suppression of PrPSc replication in the LRS. Although, a rebound of PrPSc presence occurred when the Mab 6D11 treatment was stopped, passively immunized mice showed a prolongation of the incubation period by 36.9% (p<0.0001) and a significant decrease in CNS pathology compared to control groups receiving vehicle or murine IgG. Our results indicate that antibody-based therapeutic strategies can be used, even on a short-term basis, to delay or prevent disease in subjects accidentally exposed to prions.

Sadowski, Martin J.; Pankiewicz, Joanna; Prelli, Frances; Scholtzova, Henrieta; Spinner, Daryl S.; Kascsak, Regina B.; Kascsak, Richard J.; Wisniewski, Thomas

2009-01-01

125

A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia  

Microsoft Academic Search

The hematopoietic stem cell underlying acute myeloid leukemia (AML) is contro- versial. Flow cytometry and the DNA- binding dye Hoechst 33342 were previ- ously used to identify a distinct subset of murine hematopoietic stem cells, termed the side population (SP), which rapidly expels Hoechst dye and can reconstitute the bone marrow of lethally irradiated mice. Here, the prevalence and patho-

Gerald G. Wulf; Rui-Yu Wang; Ingrid Kuehnle; Douglas Weidner; Frank Marini; Malcolm K. Brenner; Michael Andreeff; Margaret A. Goodell

2001-01-01

126

Subsets, expansion and activation of myeloid-derived suppressor cells  

Microsoft Academic Search

Tumor cells and microorganisms manipulate the immune system to minimize any counter response in order to survive. Myeloid-derived\\u000a suppressor cells (MDSC) in the mouse represent activated Gr-1+ CD11b+ myeloid precursor cells. Activation may occur through endogenous or exogenous factors leading to the suppression of immune\\u000a responses. Under steady state conditions the same precursors differentiate into dendritic cells, macrophages and neutrophils.

Eliana Ribechini; Verena Greifenberg; Sarah Sandwick; Manfred B. Lutz

2010-01-01

127

Control of myeloid differentiation and survival by Stats  

Microsoft Academic Search

Hematopoiesis involves a complex array of growth factors that regulate the survival and proliferation of immature progenitors, influence differentiation commitment, and modulate end-stage cell functions. This mini-review is focused on the role of Stat activation in the development of myeloid cells in response to hematopoietic cytokines. Much of the evidence implicating Stats in these cellular processes comes from studies of

Thomas E Smithgall; Scott D Briggs; Steven Schreiner; Edwina C Lerner; Haiyun Cheng; Matthew B Wilson

2000-01-01

128

Addition of plerixafor to mobilization regimens in autologous peripheral blood stem cell transplants does not affect the correlation of preharvest hematopoietic precursor cell enumeration with first-harvest CD34+ stem cell yield.  

PubMed

The CXCR4 antagonist plerixafor is increasingly used in the mobilization regimens for autologous peripheral blood stem cell (PBSC) transplantation. This agent may mobilize a different subset of the stem cell population than traditional regimens, such as growth factors (with and without chemotherapy). Thus, it is important to determine whether plerixafor has an effect on the utility of measurements used to predict the yield of CD34(+) cells, usually either preharvest peripheral blood CD34(+) enumeration by flow cytometry or hematopoietic precursor cell (HPC) enumeration by automated hematology analysis. Although HPC enumeration has a weaker correlation with first-harvest CD34(+) cell yield, this parameter still plays an important role in the timing of apheresis procedures for autologous PBSC transplantation because of its technical simplicity and low cost. In the present study, we retrospectively examined the correlation of HPC measurements with CD34(+) cell yields in patients with multiple myeloma and lymphoma undergoing autologous PBSC transplantation, and investigated how the mobilization regimen affected these results. We found that the correlation coefficients ranged from 0.5877 to 0.7668 and were not significantly impacted by differences in diagnosis or inclusion of plerixafor in the mobilization regimen. The predictive ability of HPC enumeration for various target yields was also examined, and receiver-operating characteristic curves were generated. An HPC cutoff of 20 should result in adequate initial CD34(+) cell yields (>2.5 × 10(6) cell/kg) in >80% of autologous donors with or without plerixafor. This study confirms the utility of HPC enumeration in prediction of adequate initial cell yields, and demonstrates that this utility is maintained regardless of whether or not plerixafor is included in the mobilization regimen. PMID:22796644

Villa, Carlos H; Shore, Tsiporah; Van Besien, Koen; Cushing, Melissa

2012-07-13

129

Targeting NF-kappaB activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells.  

PubMed

Acute myeloid leukemia (AML) cells are characterized by a constitutive and abnormal activation of the nuclear factor-kappaB (NF-kappaB) transcription factor. This study, conducted in vitro on 18 patients, shows that targeting the IKB kinase 2 (IKK2) kinase with the specific pharmacologic inhibitor AS602868 to block NF-kappaB activation led to apoptosis of human primary AML cells. Moreover, AS602868 potentiated the apoptotic response induced by the current chemotherapeutic drugs doxorubicin, cytarabine, or etoposide (VP16). AS602868-induced cell death was associated with rupture of the mitochondrial transmembrane potential and activation of cellular caspases. NF-kappaB inhibition did not affect normal CD34+ hematopoietic precursors, suggesting that it could represent a new adjuvant strategy for AML treatment. PMID:15454494

Frelin, Catherine; Imbert, Véronique; Griessinger, Emmanuel; Peyron, Annie-Claude; Rochet, Nathalie; Philip, Patrick; Dageville, Christian; Sirvent, Anne; Hummelsberger, Michaël; Bérard, Etienne; Dreano, Michel; Sirvent, Nicolas; Peyron, Jean-François

2004-09-28

130

Cell processing engineering for ex vivo expansion of hematopoietic cells: a review  

Microsoft Academic Search

The cell processing engineering for ex vivo expansion of hematopoietic cells is reviewed. All hematopoietic cells of different lineages and\\/or at various stages of differentiation are derived from the same precursor, pluripotent hematopoietic stem cells. Bone marrow stromal cells promote and regulate the self-renewal, commitment, differentiation, and proliferation of stem cells and progenitors through their secreted extracellular matrices and cytokine

Toshiomi Yoshida; Mutsumi Takagi

2004-01-01

131

PU.1 Functions in a Cell-Autonomous Manner to Control the Differentiation of Multipotential Lymphoid–Myeloid Progenitors  

Microsoft Academic Search

Transcription factor PU.1 is required for the development of lymphoid and myeloid progenitors during fetal hematopoiesis. By generating chimeric animals using PU.1?\\/? ES cells or PU.1?\\/? hematopoietic progenitors, we demonstrate that PU.1 functions in an exclusively cell-autonomous manner to regulate the development of the lymphoid–myeloid system. Multipotential lymphoid–myeloid progenitors (AA4.1+, Lin?) are significantly reduced in PU.1?\\/? embryos and fail to

Edward W Scott; Robert C Fisher; Marilyn C Olson; Eli W Kehrli; M. Celeste Simon; Harinder Singh

1997-01-01

132

Human CD34-derived myeloid dendritic cell development requires intact phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin signaling.  

PubMed

Dendritic cells (DCs) are composed of different subsets that exhibit distinct functionality in the induction and regulation of immune responses. The myeloid DC subsets, including interstitial DCs and Langerhans cells (LCs), develop from CD34+ hematopoietic progenitors via direct DC precursors or monocytes. The molecular mechanisms regulating DC development are still largely unknown and mostly studied in mice. Phosphatidylinositol 3-kinase (PI3K) regulates multiple processes in myeloid cells. This study investigated the role of PI3K signaling in the development of human CD34-derived myeloid DCs. Pharmacologic inhibition of PI3K or one of its downstream targets mTOR reduced interstitial DC and LC numbers in vitro. Increased activity of this signaling module by introduction of constitutively active protein kinase B (PKB/c-Akt) increased the yields of human DC precursors in vitro as well as in transplanted beta2-microglobulin-/- NOD/SCID mice in vivo. Signaling inhibition during differentiation did not affect the acquisition of a DC phenotype, whereas proliferation and survival strongly depended on intact PI3K-PKB-mTOR signaling. Interestingly, however, this pathway became redundant for survival regulation upon terminal differentiation, which was associated with an altered expression of apoptosis regulating genes. Although dispensable for costimulatory molecule expression, the PI3K-PKB-mTOR signaling module was required for other important processes associated with DC function, including Ag uptake, LPS-induced cytokine secretion, CCR7 expression, and T cell stimulation. Thus, PI3K-PKB-mTOR signaling plays a crucial role in the development of functional CD34-derived myeloid DCs. These findings could be used as a strategy to manipulate DC subset distribution and function to regulate immunity. PMID:20488790

van de Laar, Lianne; Buitenhuis, Miranda; Wensveen, Felix M; Janssen, Harry L A; Coffer, Paul J; Woltman, Andrea M

2010-05-19

133

Acute Myeloid Leukemia  

MedlinePLUS

... a third party. HPF: SEER Stat Fact Sheets: Acute Myeloid Leukemia Cancer: It is estimated that 14,590 men ... 10,370 men and women will die of acute myeloid leukemia in 2013 1 X Close Table I-1 ( ...

134

Hypocellular acute myeloid leukemia in adults: analysis of the clinical outcome of 123 patients  

PubMed Central

Background The hypocellular variant of acute myeloid leukemia accounts for less than 10% of all cases of adult acute myeloid leukemia. It is defined by having less than 20 percent of cellular bone marrow in a biopsy at presentation. It is unclear in the literature whether the outcome of hypocellular acute myeloid leukemia differs from that of non-hypocellular acute myeloid leukemia. Design and Methods We retrospectively analyzed all the cases reported to be hypocellular acute myeloid leukemia between 2000 and 2009. A second pathology review was conducted and the diagnosis was confirmed in all cases. Results One hundred twenty-three (9%) patients were identified: patients with hypocellular acute myeloid leukemia were older than those with non-hypocellular acute myeloid leukemia (P=0.009) and more frequently presented with cytopenias (P<0.001). Forty-one patients with hypocellular acute myeloid leukemia had an antecedent hematologic disorder and 11 patients had received prior chemo-radiotherapy for non-hematopoietic neoplasms. On multivariate analysis, overall survival, remission duration and event-free survival were comparable to those of other patients with acute myeloid leukemia. Conclusions The outcome of hypocellular acute myeloid leukemia does not differ from that of non-hypocellular acute myeloid leukemia.

Al-Kali, Aref; Konoplev, Sergej; Lin, Erpei; Kadia, Tapan; Faderl, Stefan; Ravandi, Farhad; Ayoubi, Mohamad; Brandt, Mark; Cortes, Jorge E.; Kantarjian, Hagop; Borthakur, Gautam

2012-01-01

135

Cell surface marker phenotypes and gene expression profiles of murine radiation-induced acute myeloid leukemia stem cells are similar to those of common myeloid progenitors.  

PubMed

Radiation exposure induces acute myeloid leukemia (AML) in humans and mice. Recent studies postulated that AML stem cells of spontaneous human AML arise from hematopoietic stem cells. However, other studies support the possibility that short-lived committed progenitors transform into AML stem cells, accompanied by a particular gene mutation. It remains unclear whether AML stem cells are present in radiation-induced AML, and information regarding AML-initiating cells is lacking. In this study, we identified and analyzed AML stem cells of mice with radiation-induced AML. The AML stem cells were identified by transplanting 100 bone marrow cells from mice with radiation-induced AML. We injected 100 cells of each of seven cell populations corresponding to different stages of hematopoietic cell differentiation and compared the latencies of AMLs induced in recipient mice. The identified radiation-induced AML stem cells frequently displayed similarities in both CD antigen and gene expression profiles with normal common myeloid progenitors. The number of common myeloid progenitor-like AML stem cells was significantly increased in mice with radiation-induced AML, but the progeny of common myeloid progenitors was decreased. In addition, analysis of radiation effects on the hematopoietic system showed that common myeloid progenitor cells were extremely radiosensitive and that their numbers remained at low levels for more than 2 months after radiation exposure. Our results suggest that murine radiation-induced AML stem cells arise from radiosensitive cells at a common myeloid progenitor stage. PMID:21692655

Hirouchi, Tokuhisa; Akabane, Miyuki; Tanaka, Satoshi; Braga-Tanaka, Ignacia; Todate, Akiko; Ichinohe, Kazuaki; Oghiso, Yohichi; Tanaka, Kimio

2011-06-21

136

The homeodomain transcription factor Prep1 (pKnox1) is required for hematopoietic stem and progenitor cell activity.  

PubMed

Most of the hypomorphic Prep1(i/i) embryos (expressing 3-10% of the Prep1 protein), die between E17.5 and P0, with profound anemia, eye malformations and angiogenic anomalies [Ferretti, E., Villaescusa, J.C., Di Rosa, P., Fernandez-Diaz, L.-C., Longobardi, E., Mazzieri, R., Miccio, A., Micali, N., Selleri, L., Ferrari G., Blasi, F. (2006). Hypomorphic mutation of the TALE gene Prep1 (pKnox1) causes a major reduction of Pbx and Meis proteins and a pleiotropic embryonic phenotype. Mol. Cell. Biol. 26, 5650-5662]. We now report on the hematopoietic phenotype of these embryos. Prep1(i/i) fetal livers (FL) are hypoplastic, produce less common myeloid progenitors colonies (CFU-GEMM) in cytokine-supplemented methylcellulose and have an increased number of B-cells precursors that differentiate poorly. Prep1(i/i) FL is able to protect lethally irradiated mice only at high cell doses but the few protected mice show major anomalies in all hematopoietic lineages in both bone marrow (BM) and peripheral organs. Prep1(i/i) FL cells compete inefficiently with wild type bone marrow in competitive repopulation experiments, suggesting that the major defect lies in long-term repopulating hematopoietic stem cells (LTR-HSC). Indeed, wt embryonic expression of Prep1 in the aorta-gonad-mesonephros (AGM) region, fetal liver (FL), cKit(+)Sca1(+)Lin(-)AA4.1(+) (KSLA) cells and B-lymphocytes precursors agrees with the observed phenotype. We therefore conclude that Prep1 is required for a correct and complete hematopoiesis. PMID:17904118

Di Rosa, Patrizia; Villaescusa, J Carlos; Longobardi, Elena; Iotti, Giorgio; Ferretti, Elisabetta; Diaz, Victor M; Miccio, Annarita; Ferrari, Giuliana; Blasi, Francesco

2007-08-24

137

Myeloid malignancies: mutations, models and management  

PubMed Central

Myeloid malignant diseases comprise chronic (including myelodysplastic syndromes, myeloproliferative neoplasms and chronic myelomonocytic leukemia) and acute (acute myeloid leukemia) stages. They are clonal diseases arising in hematopoietic stem or progenitor cells. Mutations responsible for these diseases occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. CBL, FLT3, JAK2, RAS), transcription factors (e.g. CEBPA, ETV6, RUNX1), epigenetic regulators (e.g. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. SF3B1, SRSF2). Large-scale sequencing efforts will soon lead to the establishment of a comprehensive repertoire of these mutations, allowing for a better definition and classification of myeloid malignancies, the identification of new prognostic markers and therapeutic targets, and the development of novel therapies. Given the importance of epigenetic deregulation in myeloid diseases, the use of drugs targeting epigenetic regulators appears as a most promising therapeutic approach.

2012-01-01

138

A novel myeloid-like NK cell progenitor in human umbilical cord blood  

Microsoft Academic Search

Natural killer (NK) cell differentiation from pluripotent CD34 human hematopoietic stem cells or oligopotent lymphoid pro- genitors has already been reported. In the present study, long-term cultures of the CD56\\/CD34 myeloid-like adherent cell fraction (ACF) from umbilical cord blood (UCB), characterized by the expression of CD14 as well as other myeloid markers, were set up with flt3 ligand (FL) and

Sonia A. Perez; Panagiota A. Sotiropoulou; Dimitra G. Gkika; Louisa G. Mahaira; Dimitrios K. Niarchos; Angelos D. Gritzapis; Yiannis G. Kavalakis; Aris I. Antsaklis; Constantin N. Baxevanis; Michael Papamichail

2003-01-01

139

Hedgehog Signaling Is Dispensable for Adult Murine Hematopoietic Stem Cell Function and Hematopoiesis  

PubMed Central

SUMMARY We report the unexpected finding that loss of Hh signaling through conditional deletion of Smoothened (Smo) in the adult hematopoietic compartment has no apparent effect on adult hematopoiesis, including peripheral blood count, number or cell-cycle status of stem or progenitor cells, hematopoietic colony-forming potential, long-term repopulating activity in competitive repopulation assays, or stress response to serial 5-fluorouracil treatment. Furthermore, pharmacologic inhibition of Hh signaling with a potent and selective small molecule antagonist has no substantive effect on hematopoiesis in the mouse. In addition, Hh signaling is not required for the development of MLL-AF9-mediated acute myeloid leukemia (AML). Taken together, these data demonstrate that Hh signaling is dispensable for normal hematopoietic development and hematopoietic stem cell function, indicating that targeting of Hh signaling in solid tumors is not likely to result in hematopoietic toxicity. Furthermore, the Hh pathway may not be a compelling target in certain hematopoietic malignancies.

Hofmann, Inga; Stover, Elizabeth H.; Cullen, Dana E.; Mao, Junhao; Morgan, Kelly J.; Lee, Benjamin H.; Kharas, Michael G.; Miller, Peter G.; Cornejo, Melanie G.; Okabe, Rachel; Armstrong, Scott A.; Ghilardi, Nico; Gould, Stephen; de Sauvage, Frederic J.; McMahon, Andrew P.; Gilliland, D. Gary

2010-01-01

140

Maxillo-ethmoidal chloroma in acute myeloid leukaemia: Case report  

PubMed Central

Summary Chloroma, also called Granulocytic Sarcoma or Myeloid Sarcoma, is a rare malignant extra-medullary neoplasm of myeloid precursor cells. It is usually associated with myeloproliferative disorders but its appearance may precede the onset of leukaemia. Chloroma may be found in several extracranial sites. Involvement of the head and neck region is uncommon. Differential diagnosis is often difficult and includes acute lymphoblastic leukaemia, large cell NHL, lymphoblastic lymphoma and Ewing’s sarcoma. The case is presented of a maxillo-ethmoidal chloroma occurring in a case of poor prognosis acute myeloid leukaemia, emphasizing the clinical and cyto-histological features and problems concerning differential diagnosis.

Ferri, E; Minotto, C; Ianniello, F; Cavaleri, S; Armato, E; Capuzzo, P

2005-01-01

141

Differentiation Therapy of Acute Myeloid Leukemia  

PubMed Central

Acute Myeloid Leukemia (AML) is a predominant acute leukemia among adults, characterized by accumulation of malignantly transformed immature myeloid precursors. A very attractive way to treat myeloid leukemia, which is now called ‘differentiation therapy’, was proposed as in vitro studies have shown that a variety of agents stimulate differentiation of the cell lines isolated from leukemic patients. One of the differentiation-inducing agents, all-trans retinoic acid (ATRA), which can induce granulocytic differentiation in myeloid leukemic cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a t(15;17)(q22;q12) chromosomal translocation. Because differentiation therapy using ATRA has significantly improved prognosis for patients with APL, many efforts have been made to find alternative differentiating agents. Since 1,25-dihydroxyvitamin D3 (1,25D) is capable of inducing in vitro monocyte/macrophage differentiation of myeloid leukemic cells, clinical trials have been performed to estimate its potential to treat patients with AML or myelodysplastic syndrome (MDS). Unfortunately therapeutic concentrations of 1,25D can induce potentially fatal systemic hypercalcemia, thus limiting clinical utility of that compound. Attempts to overcome this problem have focused on the synthesis of 1,25D analogs (VDAs) which retain differentiation inducing potential, but lack its hypercalcemic effects. This review aims to discuss current problems and potential solutions in differentiation therapy of AML.

Gocek, Elzbieta; Marcinkowska, Ewa

2011-01-01

142

The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases  

Microsoft Academic Search

Advances in the understanding of the cells of the hematopoietic system have provided a rich basis for improving clini- cal hematopoietic cell transplants; find- ing and using proteins and molecules to amplify or suppress particular blood cell types; understanding the stepwise pro- gression of preleukemic stages leading first to chronic myeloid disorders, then the emergence of acute blastic leuke- mias;

Irving L. Weissman; Judith A. Shizuru; G. Stoll; C. Kleinschnitz; B. Nieswandt; L. M. Kuijk; J. M. Beekman; J. Koster; H. R. Waterham; J. Frenkel; P. J. Coffer; F. Ciceri; M. Labopin; F. Aversa; J. M. Rowe; D. Bunjes; P. Lewalle; A. Nagler; P. Di Bartolomeo; J. F. Lacerda; M. T. L. Stanghellini; E. Polge; F. Frassoni; M. F. Martelli; V. Rocha

2008-01-01

143

Molecular pathogenesis of AML (mouse models of acute myeloid leukemia with AML1ETO fusion proteins)  

Microsoft Academic Search

Acute myeloid leukemia (AML) is a common hematopoietic malignancy characterized by the abnormal proliferation and differentiation\\u000a of myeloid progenitor cells. The fusion geneAML1-ETO is a product of t(8;21)(q22;q22) chromosomal translocation, one of the most common chromosomal translocations associated\\u000a with acute myeloid leukemia Therefore, analyzing the molecular mechanism of AML1-ETO in the process of AML development will\\u000a provide valuable information to

Dong-Er Zhang

2002-01-01

144

Mapping of MN1 Sequences Necessary for Myeloid Transformation  

PubMed Central

The MN1 oncogene is deregulated in human acute myeloid leukemia and its overexpression induces proliferation and represses myeloid differentiation of primitive human and mouse hematopoietic cells, leading to myeloid leukemia in mouse models. To delineate the sequences within MN1 necessary for MN1-induced leukemia, we tested the transforming capacity of in-frame deletion mutants, using retroviral transduction of mouse bone marrow. We found that integrity of the regions between amino acids 12 to 458 and 1119 to 1273 are required for MN1’s in vivo transforming activity, generating myeloid leukemia with some mutants also producing T-cell lympho-leukemia and megakaryocytic leukemia. Although both full length MN1 and a mutant that lacks the residues between 12–228 (?12–228 mutant) repressed myeloid differentiation and increased myeloproliferative activity in vitro, the mutant lost its transforming activity in vivo. Both MN1 and ?12–228 increased the frequency of common myeloid progentiors (CMP) in vitro and microarray comparisons of purified MN1-CMP and ?12–228-CMP cells showed many differentially expressed genes including Hoxa9, Meis1, Myb, Runx2, Cebpa, Cebpb and Cebpd. This collection of immediate MN1-responsive candidate genes distinguishes the leukemic activity from the in vitro myeloproliferative capacity of this oncoprotein.

Kandilci, Ayten; Surtel, Jacqueline; Janke, Laura; Neale, Geoffrey; Terranova, Sabrina; Grosveld, Gerard C.

2013-01-01

145

Transporter-Mediated Protection against Thiopurine-Induced Hematopoietic Toxicity  

Microsoft Academic Search

Thiopurines are effective immunosuppressants and antican- cer agents, but intracellular accumulation of their active metabolites (6-thioguanine nucleotides, 6-TGN) causes dose- limiting hematopoietic toxicity. Thiopurine S-methyltransferase deficiency is known to exacerbate thiopurine toxicity. How- ever, many patients are highly sensitive to thiopurines for unknown reasons. We show that multidrug-resistance protein 4 (Mrp4) is abundant in myeloid progenitors and tested the role

Partha Krishnamurthy; Matthias Schwab; Kazumasa Takenaka; Deepa Nachagari; Jessica Morgan; Mark Leslie; Weinan Du; Kelli Boyd; Meyling Cheok; Hiromitsu Nakauchi; Catia Marzolini; Richard B. Kim; Balasubramanian Poonkuzhali; Erin Schuetz; William Evans; Mary Relling; John D. Schuetz

146

IGFBP2 Supports ex vivo Expansion of Hematopoietic Stem Cells  

Microsoft Academic Search

\\u000a The hematopoietic stem cell (HSC), through proliferation and differentiation, gives rise to all lymphoid, myeloid, and erythroid\\u000a cells. Successful HSC transplantation is often limited by the numbers of HSCs, and robust methods to expand HSCs ex vivo are\\u000a needed (Bryder et al. 2006; Tse et al. 2008). We demonstrated that insulin-like growth factor binding protein 2 (IGFBP2),\\u000a secreted by a

HoangDinh Huynh; Megan Kaba; Sonali Rudra; Junke Zheng; Catherine J. Wu; Harvey F. Lodish; Cheng Cheng Zhang

147

A Case of Inguinal Sparganosis Mimicking Myeloid Sarcoma  

PubMed Central

We report here a case of inguinal sparganosis, initially regarded as myeloid sarcoma, diagnosed in a patient undergone allogeneic hematopoietic transplantation (HSCT). A 56-year-old male patient having myelodysplastic syndrome was treated with allogeneic HSCT after myeloablative conditioning regimen. At day 5 post-HSCT, the patient complained of a painless palpable mass on the left scrotum and inguinal area. Pelvic magnetic resonance imaging and computed tomography revealed suspected myeloid sarcoma. Gun-biopsy was performed, and the result revealed eosinophilic infiltrations without malignancy. Subsequent serologic IgG antibody test was positive for sparganum. Excisional biopsy as a therapeutic diagnosis was done, and the diagnosis of sparganosis was confirmed eventually. This is the first report of sparganosis after allogeneic HSCT mimicking myeloid sarcoma, giving a lesson that the physicians have to consider the possibility of sparganosis in this clinical situation and perform adequate diagnostic and therapeutic approaches.

Yeo, Jin Yeob; Han, Jee Young; Lee, Jung Hwan; Park, Young Hoon; Lim, Joo Han; Lee, Moon Hee; Kim, Chul Soo

2012-01-01

148

Sox4 cooperates with CREB in myeloid transformation.  

PubMed

The cAMP response element-binding protein (CREB) is a nuclear transcription factor that is critical for normal and neoplastic hematopoiesis. Previous studies have demonstrated that CREB is a proto-oncogene whose overexpression promotes cellular proliferation in hematopoietic cells. Transgenic mice that overexpress CREB in myeloid cells develop a myeloproliferative disease with splenomegaly and aberrant myelopoiesis. However, CREB overexpressing mice do not spontaneously develop acute myeloid leukemia. In this study, we used retroviral insertional mutagenesis to identify genes that accelerate leukemia in CREB transgenic mice. Our mutagenesis screen identified several integration sites, including oncogenes Gfi1, Myb, and Ras. The Sox4 transcription factor was identified by our screen as a gene that cooperates with CREB in myeloid leukemogenesis. We show that the transduction of CREB transgenic mouse bone marrow cells with a Sox4 retrovirus increases survival and self-renewal of cells in vitro. Furthermore, leukemic blasts from the majority of acute myeloid leukemia patients have higher CREB, phosphorylated CREB, and Sox 4 protein expression. Sox4 transduction of mouse bone marrow cells results in increased expression of CREB target genes. We also demonstrate that CREB is a direct target of Sox4 by chromatin immunoprecipitation assays. These results indicate that Sox4 and CREB cooperate and contribute to increased proliferation of hematopoietic progenitor cells. PMID:22627767

Sandoval, Salemiz; Kraus, Christina; Cho, Er-Chieh; Cho, Michelle; Bies, Juraj; Manara, Elena; Accordi, Benedetta; Landaw, Elliot M; Wolff, Linda; Pigazzi, Martina; Sakamoto, Kathleen M

2012-05-24

149

Cell intrinsic alterations underlie hematopoietic stem cell aging  

PubMed Central

Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.

Rossi, Derrick J.; Bryder, David; Zahn, Jacob M.; Ahlenius, Henrik; Sonu, Rebecca; Wagers, Amy J.; Weissman, Irving L.

2005-01-01

150

Acute Myeloid Leukemia  

MedlinePLUS

What is acute myeloid leukemia (AML)? The second most common type of acute leukemia in adults, AML is a cancer of the blood ... cancer.org (American Cancer Society). Type the keywords acute myeloid leukemia into the search box. What kinds of questions ...

151

A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia  

Microsoft Academic Search

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may pro- mote proliferation and survival of leuke- mic blasts. This concept represented the rationale for

Walter Fiedler; Rolf Mesters; Heike Tinnefeld; Sonja Loges; Peter Staib; Ulrich Duhrsen; Michael Flasshove; Oliver G. Ottmann; Wolfram Jung; Franco Cavalli; Rolf Kuse; Joerg Thomalla; Hubert Serve; Anne M. O'Farrell; Mark Jacobs; Nicoletta M. Brega; Paul Scigalla; Dieter K. Hossfeld; Wolfgang E. Berdel

2003-01-01

152

FAM20: an evolutionarily conserved family of secreted proteins expressed in hematopoietic cells  

Microsoft Academic Search

BACKGROUND: Hematopoiesis is a complex developmental process controlled by a large number of factors that regulate stem cell renewal, lineage commitment and differentiation. Secreted proteins, including the hematopoietic growth factors, play critical roles in these processes and have important biological and clinical significance. We have employed representational difference analysis to identify genes that are differentially expressed during experimentally induced myeloid

Demet Nalbant; Hyewon Youn; S Isil Nalbant; Savitha Sharma; Everardo Cobos; Elmus G Beale; Yang Du; Simon C Williams

2005-01-01

153

De novo postallogeneic hematopoietic stem cell transplant membranous nephropathy.  

PubMed

We report membranous nephropathy in a 61-year-old man after allogeneic hematopoietic stem cell transplant without chronic graft-versus-host disease. A diagnosis of acute myeloid leukemia was made, and the patient received hematopoietic stem cell transplants, twice, from different donors. The first donor was his brother and the second donor was an unrelated man. Human leukocyte antigens between donors and recipient were fully matched. His clinical course was stable without acute or chronic graft-versus-host disease or relapse of acute myeloid leukemia with tacrolimus after the second hematopoietic stem cell transplant. Six months after the second hematopoietic stem cell transplant, tacrolimus was decreased gradually and discontinued because of tacrolimus-induced liver dysfunction. Three months after discontinuing the tacrolimus, the patient developed edema in his leg. The results of a blood analysis showed that plasma albumin level was 21 g/L and plasma total cholesterol level was 11.5 mmol/L, while results from a urinalysis showed proteinuria of 5.6 g/d without hematuria. No abnormalities in the skin, mucosal tissues, and other organs suggestive of chronic graft-versus-host disease were seen. A renal biopsy was done to investigate the cause, which revealed renal disease. Electron microscopic analysis showed dense deposits in the subepithelial region in all glomeruli. Immunofluorescence analysis showed the deposition of IgG4 and C3c in the subepithelial space of all glomeruli. Membranous nephropathy was diagnosed. He then was administered prednisolone at a dosage of 45 mg/d (0.7 mg/kg/d). After prednisolone treatment, urine protein and hypoalbuminemia were markedly improved, and his leg edema disappeared. These results suggest that this membranous nephropathy may have been de novo membranous nephropathy after hematopoietic stem cell transplant because it developed after hematopoietic stem cell transplants without chronic graft-versus-host disease. PMID:22809119

Numata, Akihiko; Morishita, Yoshiyuki; Mori, Masaki; Saito, Osamu; Takemoto, Fumi; Ando, Yasuhiro; Muto, Shigeaki; Yumura, Wako; Kusano, Eiji

2012-07-18

154

Multipotent neural precursors express neural and hematopoietic factors, and enhance ex vivo expansion of cord blood CD34+ cells, colony forming units and NOD/SCID-repopulating cells in contact and noncontact cultures.  

PubMed

In view of the possible crosstalks between hematopoiesis and neuropoiesis, we evaluated two microenvironments, murine neonatal neural cell line C17.2 and primary embryonic aorta-gonad-mesonephros (AGM) stromal cells, on the ex vivo expansion of CD34+ cells from human cord blood. In a contact culture system, C17.2 or AGM cells significantly enhanced the expansion of CD34+ cells to a panel of early and committed hematopoietic progenitor cells. In a noncontact transwell system, pre-established C17.2 cells significantly increased the expansion of total nucleated cells, CD34+ cells and multilineage colony forming cells (P<0.01). Expanded cells were infused into nonobese diabetic/severe-combined immunodeficient mice. The engraftment of human (hu)CD45+ cells in the bone marrow of these mice was consistently higher in all the 10 experiments conducted with the support of C17.2 cells when compared with those in respective control groups (11.9 vs 2.43%, P=0.03). Using RT-PCR and Southern blot analysis, we showed that AGM and C17.2 cells expressed a panel of hematopoietic, bone morphogenetic and neurotrophic factors. Our data provided the first evidence on the promoting effects of a neural progenitor cell line on hematopoiesis at a noncontact condition. The mechanism could be mediated by the expression of multilineage regulatory factors. PMID:15496976

Li, K; Lee, S M; Su, R J; Zhang, X B; Yuen, P M P; Li, C K; Yang, M; Tsang, K S; James, A E; Tse, Y H J; Ng, L Y W; Fok, T F

2005-01-01

155

Multilineage Priming of Enhancer Repertoires Precedes Commitment to the B and Myeloid Cell Lineages in Hematopoeitic Progenitors  

PubMed Central

SUMMARY Recent studies have documented genome-wide binding patterns of transcriptional regulators and their associated epigenetic marks in hematopoietic cell lineages. In order to determine how epigenetic marks are established and maintained during developmental progression, we have generated long-term cultures of hematopoietic progenitors by enforcing the expression of the E-protein antagonist Id2. Hematopoietic progenitors that express Id2 are multipotent and readily differentiate upon withdrawal of Id2 expression into committed B lineage cells, thus indicating a causative role for E2A (Tcf3) in promoting the B cell fate. Genome-wide analyses revealed that a substantial fraction of lymphoid and myeloid enhancers are pre-marked by the poised or active enhancer mark H3K4Me1 in multipotent progenitors. Thus, in hematopoietic progenitors, multilineage priming of enhancer elements precedes commitment to the lymphoid or myeloid cell lineages.

Mercer, Elinore M.; Lin, Yin C.; Benner, Christopher; Jhunjhunwala, Suchit; Dutkowski, Janusz; Flores, Martha; Sigvardsson, Mikael; Ideker, Trey; Glass, Christopher K.; Murre, Cornelis

2011-01-01

156

Immunotherapy for acute myeloid leukemia.  

PubMed

Immunotherapeutic strategies have become part of standard cancer treatment. Chimeric and humanized antibodies have demonstrated activity against a variety of tumors. Although the humanized anti-CD33 antibody HuM195 has only modest activity against overt acute myeloid leukemia (AML), it can eliminate minimal residual disease in acute promyelocytic leukemia. High-dose radioimmunotherapy with b-particle-emitting isotopes targeting CD33, CD45, and CD66 can potentially allow intensification of antileukemic therapy before hematopoietic stem cell transplantation. Conversely, a-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumor cell kill while sparing surrounding normal tissues. Targeted chemotherapy with the anti-CD33- calicheamicin construct gemtuzumab ozogamicin has produced remissions in relapsed AML and appears promising when used in combination with standard chemotherapy for newly diagnosed AML. T-cell recognition of peptide antigens presented on the cell surface in combination with major histocompatibility complex antigen provides another potentially promising approach for the treatment of AML. PMID:16091194

Jurcic, Joseph G

2005-09-01

157

Shared and Distinct Functions of the Transcription Factors IRF4 and IRF8 in Myeloid Cell Development  

Microsoft Academic Search

Interferon regulatory factor (IRF) 8 and IRF4 are structurally-related, hematopoietic cell-specific transcription factors that cooperatively regulate the differentiation of dendritic cells and B cells. Whilst in myeloid cells IRF8 is known to modulate growth and differentiation, the role of IRF4 is poorly understood. In this study, we show that IRF4 has activities similar to IRF8 in regulating myeloid cell development.

Michio Yamamoto; Takayuki Kato; Chie Hotta; Akira Nishiyama; Daisuke Kurotaki; Masahiro Yoshinari; Masamichi Takami; Motohide Ichino; Masatoshi Nakazawa; Toshifumi Matsuyama; Ryutaro Kamijo; Seiichi Kitagawa; Keiko Ozato; Tomohiko Tamura; Kevin D. Bunting

2011-01-01

158

The TAL1/SCL Transcription Factor Regulates Cell Cycle Progression and Proliferation in Differentiating Murine Bone Marrow Monocyte Precursors?  

PubMed Central

Monocytopoiesis involves the stepwise differentiation in the bone marrow (BM) of common myeloid precursors (CMPs) to monocytes. The basic helix-loop-helix transcription factor TAL1/SCL plays a critical role in other hematopoietic lineages, and while it had been reported to be expressed by BM-derived macrophages, its role in monocytopoiesis had not been elucidated. Using cell explant models of monocyte/macrophage (MM) differentiation, one originating with CMPs and the other from more committed precursors, we characterized the phenotypic and molecular consequences of inactivation of Tal1 expression ex vivo. While Tal1 knockout had minimal effects on cell survival and slightly accelerated terminal differentiation, it profoundly inhibited cell proliferation and decreased entry into and traversal of the G1 and S phases. In conjunction, steady-state levels of p16(Ink4a) mRNA were increased and those of Gata2 mRNA decreased. Chromatin immunoprecipitation analysis demonstrated the association of Tal1 and E47, one of its E protein DNA-binding partners, with an E box-GATA sequence element in intron 4 of the Gata2 gene and with three E boxes upstream of p16(Ink4a). Finally, wild-type Tal1, but not a DNA binding-defective mutant, rescued the proliferative defect in Tal1-null MM precursors. These results document the importance of this transcription factor in cell cycle progression and proliferation during monocytopoiesis and the requirement for direct DNA binding in these processes.

Dey, Soumyadeep; Curtis, David J.; Jane, Stephen M.; Brandt, Stephen J.

2010-01-01

159

The TAL1/SCL transcription factor regulates cell cycle progression and proliferation in differentiating murine bone marrow monocyte precursors.  

PubMed

Monocytopoiesis involves the stepwise differentiation in the bone marrow (BM) of common myeloid precursors (CMPs) to monocytes. The basic helix-loop-helix transcription factor TAL1/SCL plays a critical role in other hematopoietic lineages, and while it had been reported to be expressed by BM-derived macrophages, its role in monocytopoiesis had not been elucidated. Using cell explant models of monocyte/macrophage (MM) differentiation, one originating with CMPs and the other from more committed precursors, we characterized the phenotypic and molecular consequences of inactivation of Tal1 expression ex vivo. While Tal1 knockout had minimal effects on cell survival and slightly accelerated terminal differentiation, it profoundly inhibited cell proliferation and decreased entry into and traversal of the G(1) and S phases. In conjunction, steady-state levels of p16(Ink4a) mRNA were increased and those of Gata2 mRNA decreased. Chromatin immunoprecipitation analysis demonstrated the association of Tal1 and E47, one of its E protein DNA-binding partners, with an E box-GATA sequence element in intron 4 of the Gata2 gene and with three E boxes upstream of p16(Ink4a). Finally, wild-type Tal1, but not a DNA binding-defective mutant, rescued the proliferative defect in Tal1-null MM precursors. These results document the importance of this transcription factor in cell cycle progression and proliferation during monocytopoiesis and the requirement for direct DNA binding in these processes. PMID:20194619

Dey, Soumyadeep; Curtis, David J; Jane, Stephen M; Brandt, Stephen J

2010-03-01

160

Multicentric extramedullary myeloid tumor  

PubMed Central

Granulocytic sarcomas or extramedullary myeloid tumors represent the soft tissue counterpart of acute myeloid leukemia. The term is used for any solid collection of leukemic cells. There have been reports of these tumors occurring before the involvement of blood or bone marrow. Our patient had simultaneous involvement of three sites, which was diagnosed on cytology. Further confirmation was done on peripheral blood and bone marrow evaluation.

Dhingra, Meetu; Radhika, K; Paul, Roshni T; Aruna, Prayaga K

2009-01-01

161

Dendritic cell vaccination in acute myeloid leukemia.  

PubMed

The prognosis of patients with acute myeloid leukemia (AML) remains dismal, with a 5-year overall survival rate of only 5.2% for the continuously growing subgroup of AML patients older than 65 years. These patients are generally not considered eligible for intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation because of high treatment-related morbidity and mortality, emphasizing the need for novel, less toxic, treatment alternatives. It is within this context that immunotherapy has gained attention in recent years. In this review, we focus on the use of dendritic cell (DC) vaccines for immunotherapy of AML. DC are central orchestrators of the immune system, bridging innate and adaptive immunity and critical to the induction of anti-leukemic immunity. We discuss the rationale and basic principles of DC-based therapy for AML and review the clinical experience that has been obtained so far with this form of immunotherapy for patients with AML. PMID:22686130

Anguille, Sébastien; Willemen, Yannick; Lion, Eva; Smits, Evelien L; Berneman, Zwi N

2012-07-01

162

Hematopoietic tissue repair under chronic low daily dose irradiation  

SciTech Connect

The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). We have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3{minus}26.3 cGy d{sup {minus}1}). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup (1), the failure to augment basic m-pair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments particularly marked within erythroid compartments. that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccomodated and either prone- or not prone to ML, subgroup 2 & 3 appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high- tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity.

Seed, T.M.

1994-12-01

163

A Large Gene Network in Immature Erythroid Cells Is Controlled by the Myeloid and B Cell Transcriptional Regulator PU.1  

Microsoft Academic Search

PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used

Sandeep N. Wontakal; Xingyi Guo; Britta Will; Minyi Shi; Debasish Raha; Milind C. Mahajan; Sherman Weissman; Michael Snyder; Ulrich Steidl; Deyou Zheng; Arthur I. Skoultchi

2011-01-01

164

Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia?  

Microsoft Academic Search

The clinical use of autologous marrow transplantation in acute myeloid leukemia (AML) has been hampered by the inability to collect adequate numbers of cells after remission induction chemotherapy and the notably delayed hematopoietic regeneration following autograft reinfusion. Here we present a study in which the feasibility of mobilizing stem cells was investigated in newly diagnosed AML. Among 96 AML patients,

E. Vellenga; WLJ van Putten; M. A. Boogaerts; S. M. G. J. Daenen; G. E. G. Verhoef; A. Hagenbeek; A. R. Jonkhoff; P. C. Huijgens; L. F. Verdonck; J van der Lelie; H. C. Schouten; J. Gmur; P. W. Wijermans; A. Gratwohl; U. Hess; M. F. Fey; B. Lowenberg

1999-01-01

165

Role of c-fes protooncogene in myeloid differentiation.  

PubMed

The main purpose of this report is to provide a review of the present knowledge on the structure, function, and possible regulatory role of c-fes in the genetic programs underlying the proliferation and differentiation of hematopoietic myeloid cells. Fes encodes a non-receptor tyrosine kinase that is highly expressed in immature and differentiated cells of the granulocytic and mono-macrophagic lineages. It is therefore possible that c-fes is involved in the signal transduction of myeloid cell differentiation, even if the specific substrates phosphorylated by this protooncogene are only poorly characterised. Several experimental models have been established to evaluate the role of c-fes in myeloid differentiation, in particular: the differentiation capacity of HL60 cells lacking the p92(c-fes) protein, the transfection of c-fes gene into K562 cells and transgenic animals overexpressing c-fes. The results obtained point to the importance of c-fes in myeloid cells, since it appears to be involved in granulocytic maturation as an antiapoptotic gene, and in macrophagic maturation as a regulatory gene. PMID:17180038

Ferrari, S; Grande, A; Manfredini, R; Tagliafico, E

1995-07-01

166

Karyotypic findings in chronic myeloid leukemia cases undergoing treatment  

PubMed Central

BACKGROUND: Chronic myeloid leukemia (CML) is a clonal myeloproliferative expansion of primitive hematopoietic progenitor cells. MATERIALS AND METHODS: In the present study, CML samples were collected from various hospitals in Amritsar, Jalandhar and Ludhiana. RESULTS: Chromosomal alterations seen in peripheral blood lymphocytes of these treated and untreated cases of CML were satellite associations, double minutes, random loss, gain of C group chromosomes and presence of marker chromosome. No aberrations were observed in control samples. Karyotypic abnormalities have also been noted in the Ph-negative cells of some patients in disease remission. CONCLUSION: This is a novel phenomenon whose prognostic implications require thorough and systematic evaluation.

Kaur, Anupam; Kaur, Simran Preet; Singh, Amarjit; Singh, Jai Rup

2012-01-01

167

Impact of hematopoietic chimerism at day +14 on engraftment after unrelated donor umbilical cord blood transplantation for hematologic malignancies  

Microsoft Academic Search

Background Cord blood transplant is a feasible treatment alternative for adult patients with hemato- logic malignancies lacking a suitable HLA-matched donor . However, the kinetics of myeloid recovery is slow, and primary graft failure cannot be detected easily early after transplantation. We investigated the impact of hematopoietic chimerism status from uns- elected marrow cells 14 days after transplantation on predicting

F. Moscardo; Jaime Sanz; Leonor Senent; Susana Cantero; Javier de la Rubia; Pau Montesinos; Dolores Planelles; Ignacio Lorenzo; Jose Cervera; Javier Palau; Miguel A. Sanz; Guillermo F. Sanz

2009-01-01

168

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes  

PubMed Central

Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the “don’t eat me” signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.

Pang, Wendy W.; Pluvinage, John V.; Price, Elizabeth A.; Sridhar, Kunju; Arber, Daniel A.; Greenberg, Peter L.; Schrier, Stanley L.; Park, Christopher Y.; Weissman, Irving L.

2013-01-01

169

Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver.  

PubMed

Liver transplantation (LT) is a cure for many liver diseases. Blood chimerism of donor origin can develop after LT, which raises the possibility of the existence of hematopoietic stem/progenitor cells (HSPCs) in the liver. We characterized the blood chimerism in a large cohort of 249 LT patients and analyzed putative HSPCs in adult human livers. The overall incidence of chimerism was 6.43%, of which 11.11% was among short-term (1 day to 6 months) and 3.77% was among long-term (6 months to 8 years) LT patients. Hematopoietic Lin(-) CD34(+) CD38(-) CD90(+) populations have been demonstrated to generate long-term lymphomyeloid grafts in transplantations. In human adult livers, we detected Lin(-) CD34(+) CD38(-) CD90(+) populations accounting for 0.03% ± 0.017% of the total single liver cells and for 0.05% ± 0.012% of CD45(+) liver cells. Both Lin(-) CD34(+) and Lin(-) CD45(+) liver cells, from extensively perfused human liver grafts, were capable of forming hematopoietic myeloid-lineage and erythroid-lineage methylcellulose colonies. More importantly, Lin(-) CD45(+) or CD45(+) liver cells could be engrafted into hematopoietic cells in an immunodeficient mouse model. These results are the first evidence of the presence of putative HSPC populations in the adult human liver, where the liver is a good ectopic niche. The discovery of the existence of HSPCs in the adult liver have implications for the understanding of extramarrow hematopoiesis, liver regeneration, mechanisms of tolerance in organ transplantation, and de novo cancer recurrence in LT patients. Conclusion: The human adult liver contains a small population of HSPCs. In LT patients, there are two types of chimerisms: transient chimerism, resulting from mature leucocytes, and long-term chimerism, derived from putative HSPCs in the liver graft. PMID:22544823

Wang, Xiao Qi; Lo, Chung Mau; Chen, Lin; Cheung, Cindy K Y; Yang, Zhen Fan; Chen, Yong Xiong; Ng, Michael N; Yu, Wan Ching; Ming, Xiaoyan; Zhang, Wu; Ho, David W Y; Chan, See Ching; Fan, Sheung Tat

2012-10-01

170

Changes in the use of hematopoietic stem cell transplantation: a model for diffusion of medical technology  

PubMed Central

Background Innovations in hematology spread rapidly. Factors affecting the speed of introduction, international diffusion, and durability of use of innovations are, however, poorly understood. Design and Methods We used data on 251,106 hematopoietic stem cell transplants from 591 teams in 36 European countries to analyze the increase and decrease in such transplants for breast cancer and chronic myeloid leukemia and the replacement of bone marrow by peripheral blood as the source of stem cells as processes of diffusion. Regression analyses were used to measure the quantitative impact of defined macro- and microeconomic factors, to look for significant associations (t-test), and to describe the coefficient of determination or explanatory content (R2). Results Gross national income per capita, World Bank category, team density, team distribution, team size, team experience and, team innovator status were all significantly associated with some or all of the changes. The analyses revealed different patterns of associations and a wide range of explanatory content. Macro- and micro-economic factors were sufficient to explain the increase of allogeneic hematopoietic stem cell transplants in general (R2 = 78.41%) and for chronic myeloid leukemia in particular (R2 = 79.39%). They were insufficient to explain the changes in stem cell source (R2 =26.79% autologous hematopoietic stem cell transplants; R2 = 9.67% allogeneic hematopoietic stem cell transplants) or the decreases in hematopoietic stem cell transplants (R2 =10.22% breast cancer; R2=33.17% chronic myeloid leukemia). Conclusions The diffusion of hematopoietic stem cell transplants is more complex than previously thought. Availability of resources, evidence, external regulations and, expectations were identified as key determinants. These data might serve as a model for diffusion of medical technology in general.

Gratwohl, Alois; Schwendener, Alvin; Baldomero, Helen; Gratwohl, Michael; Apperley, Jane; Niederwieser, Dietger; Frauendorfer, Karl

2010-01-01

171

CDC42 ACTIVITY REGULATES HEMATOPOIETIC STEM CELL AGING AND REJUVENATION  

PubMed Central

SUMMARY The functional decline in hematopoietic function seen during aging involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to aging of hematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. Here we demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC aging and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a similar status as seen in young HSCs. Our data therefore suggest a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell aging.

Florian, Maria Carolina; Dorr, Karin; Niebel, Anja; Daria, Deidre; Schrezenmeier, Hubert; Rojewski, Markus; Filippi, Marie-Dominique; Hasenberg, Anja; Gunzer, Matthias; Scharffetter-Kochanek, Karin; Zheng, Yi; Geiger, Hartmut

2012-01-01

172

[Endothelial origin for hematopoietic stem cells: a visual proof].  

PubMed

Hematopoietic stem cells (HSC) are the source of all blood cell types produced during the entire life of an organism. They appear during embryonic development, where they will transit through different successive hematopoietic organs, before to finally colonize the bone marrow. Nowadays, the precise origin of HSC remains a matter of controversy. Different HSC precursor candidates, located in different anatomical sites, have been proposed. Here, we summarize and discuss the different theories in light of the recent articles, especially those using in vivo confocal microscopy technology. PMID:22027425

Boisset, Jean-Charles; Robin, Catherine

2011-10-21

173

Allogeneic Hematopoietic Stem Cell Transplantation for a BCR-FGFR1 Myeloproliferative Neoplasm Presenting as Acute Lymphoblastic Leukemia  

PubMed Central

Hematopoietic myeloproliferative neoplasms (MPNS) with rearrangements of the receptor tyrosine kinase FGFR1 gene, located on chromosome 8p11, are uncommon and associated with diverse presentations such as atypical chronic myeloid leukemia, acute myeloid leukemia, or an acute T- or B-lymphoblastic leukemia, reflecting the hematopoietic stem cell origin of the disease. A review of MPN patients with the t(8;22) translocation that results in a chimeric BCR-FGFR1 fusion gene reveals that this disease either presents or rapidly transforms into an acute leukemia that is generally unresponsive to currently available chemotherapeutic regimens including tyrosine kinase inhibitors (TKIS). The first case of a rare BCR-FGFR1 MPN presenting in a B-acute lymphoblastic phase who underwent allogeneic hematopoietic stem cell transplantation (HSCT) with a subsequent sustained complete molecular remission is described. Allogeneic HSCT is currently the only available therapy capable of achieving long-term remission in BCR-FGFR1 MPN patients.

Haslam, Karl; Langabeer, Stephen E.; Kelly, Johanna; Coen, Natasha; O'Connell, Niamh M.; Conneally, Eibhlin

2012-01-01

174

Modeling Human Lymphoid Precursor Cell Gene Therapy in the SCID-hu Mouse  

Microsoft Academic Search

ECENT DEVELOPMENTS in gene therapy have al- lowed several advances toward rectifying common ge- netic defects; however, transduction of foreign genes into hematopoietic stem cells remains an area of study with many challenges, including efficient delivery of genes and their regulation and maintenance of Novel gene therapy strategies involving early hematopoietic precursors cannot be adequately tested in humans before use

Ramesh K. Akkina; Joseph D. Rosenblatt; Andrew G. Campbell; S. Y. Chen; Jerome A. Zack

1994-01-01

175

BCL2A1a Over-Expression in Murine Hematopoietic Stem and Progenitor Cells Decreases Apoptosis and Results in Hematopoietic Transformation  

PubMed Central

We previously reported the development of a lethal myeloid sarcoma in a non-human primate model utilizing retroviral vectors to genetically modify hematopoietic stem and progenitor cells. This leukemia was characterized by insertion of the vector provirus into the BCL2A1 gene, with resultant BCL2A1 over-expression. There is little information on the role of this anti-apoptotic member of the BCL2 family in hematopoiesis or leukemia induction. Therefore we studied the impact of Bcl2a1a lentiviral over-expression on murine hematopoietic stem and progenitor cells. We demonstrated the anti-apoptotic function of this protein in hematopoietic cells, but did not detect any impact of Bcl2a1a on in vitro cell growth or cell cycle kinetics. In vivo, we showed a higher propensity of HSCs over-expressing Bcl2a1a to engraft and contribute to hematopoiesis. Mice over-expressing Bcl2a1a in the hematologic compartment eventually developed an aggressive malignant disease characterized as a leukemia/lymphoma of B-cell origin. Secondary transplants carried out to investigate the primitive origin of the disease revealed the leukemia was transplantable. Thus, Bcl2a1 should be considered as a proto-oncogene with a potential role in both lymphoid and myeloid leukemogenesis, and a concerning site for insertional activation by integrating retroviral vectors utilized in hematopoietic stem cell gene therapy.

Geyer, Julia T.; Calado, Rodrigo T.; Aplan, Peter D.; Eckhaus, Michael A.; Dunbar, Cynthia E.

2012-01-01

176

Chimerism analysis within 6 months of allogeneic stem cell transplantation predicts relapse in acute myeloid leukemia  

Microsoft Academic Search

The role of chimerism analysis as a prognostic indicator of relapse after hematopoietic stem cell transplantation (SCT) is controversial. We monitored chimerism status by short tandem repeat-based polymerase chain reaction (PCR) in T- and non-T-cell subsets and retrospectively evaluated clinical outcome in 96 patients with acute myeloid leukemia after myeloablative (MA) or reduced-intensity conditioning SCT. Fifty-six percent of 80 patients

C Huisman; R A de Weger; L de Vries; M G J Tilanus; L F Verdonck

2007-01-01

177

Can Acute Myeloid Leukemia Be Prevented?  

MedlinePLUS

... Can acute myeloid leukemia be found early? Can acute myeloid leukemia be prevented? It’s not known what causes most cases of acute myeloid leukemia (AML). Since most leukemia patients have no known ...

178

Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia  

Microsoft Academic Search

BACKGROUND. In severe congenital neutropenia the maturation of myeloid\\u000a progenitor cells is arrested. The myelodysplastic syndrome and acute\\u000a myeloid leukemia develop in some patients with severe congenital\\u000a neutropenia. Abnormalities in the signal-transduction pathways for\\u000a granulocyte colony-stimulating factor (G-CSF) may play a part in the\\u000a progression to acute myeloid leukemia. METHODS. We isolated genomic DNA\\u000a and RNA from hematopoietic cells obtained

Fan Dong; Russell K. Brynes; Nicola Tidow; Karl Welte; Bob Löwenberg; Ivo P. Touw

1995-01-01

179

Induction of myelodysplasia by myeloid-derived suppressor cells  

PubMed Central

Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-? by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.

Chen, Xianghong; Eksioglu, Erika A.; Zhou, Junmin; Zhang, Ling; Djeu, Julie; Fortenbery, Nicole; Epling-Burnette, Pearlie; Van Bijnen, Sandra; Dolstra, Harry; Cannon, John; Youn, Je-in; Donatelli, Sarah S.; Qin, Dahui; De Witte, Theo; Tao, Jianguo; Wang, Huaquan; Cheng, Pingyan; Gabrilovich, Dmitry I.; List, Alan; Wei, Sheng

2013-01-01

180

Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT  

Microsoft Academic Search

Rapid recovery of lymphocytes after T-cell depleted hematopoietic SCT (HSCT) protects from relapse of myeloid malignancies. Whether lymphocyte reconstitution has a similar role after non-manipulated transplantation is controversial. We assessed numbers of CD4 and CD8 T-cells, natural killer (NK) cells and B-cells, before and 1, 3, 6, 12 and 24 months after T-cell replete transplantation in 345 patients. Lymphocyte subset

L Bühlmann; A S Buser; N Cantoni; S Gerull; A Tichelli; A Gratwohl; M Stern

2011-01-01

181

Engraftment of Immune-Deficient Mice with Human Hematopoietic Stem Cells  

Microsoft Academic Search

A system in which immune-deficient mice are repopulated with cells from the human myeloid lineage, and that provides an in vivo stem cell assay for human hematopoietic cells is described. Generation of the chimeric human\\/immune-deficient (HID) mice was dependent on the use of immune-deficient bg\\/nu\\/xid mice. Infusion of these mice with human bone marrow gave rise to increases in human

Suzanne Kamel-Reid; John E. Dick

1988-01-01

182

Hierarchical Differentiation of Myeloid Progenitors Is Encoded in the Transcription Factor Network  

PubMed Central

Hematopoiesis is an ideal model system for stem cell biology with advanced experimental access. A systems view on the interactions of core transcription factors is important for understanding differentiation mechanisms and dynamics. In this manuscript, we construct a Boolean network to model myeloid differentiation, specifically from common myeloid progenitors to megakaryocytes, erythrocytes, granulocytes and monocytes. By interpreting the hematopoietic literature and translating experimental evidence into Boolean rules, we implement binary dynamics on the resulting 11-factor regulatory network. Our network contains interesting functional modules and a concatenation of mutual antagonistic pairs. The state space of our model is a hierarchical, acyclic graph, typifying the principles of myeloid differentiation. We observe excellent agreement between the steady states of our model and microarray expression profiles of two different studies. Moreover, perturbations of the network topology correctly reproduce reported knockout phenotypes in silico. We predict previously uncharacterized regulatory interactions and alterations of the differentiation process, and line out reprogramming strategies.

Schroeder, Timm; Theis, Fabian J.

2011-01-01

183

Comprehensive analysis of myeloid lineage conversion using mice expressing an inducible form of C/EBP?  

PubMed Central

CCAAT/enhancer-binding protein (C/EBP) ? is a critical regulator for early myeloid differentiation. Although C/EBP? has been shown to convert B cells into myeloid lineage, precise roles of C/EBP? in various hematopoietic progenitors and stem cells still remain obscure. To examine the consequence of C/EBP? activation in various progenitors and to address the underlying mechanism of lineage conversion in detail, we established transgenic mice expressing a conditional form of C/EBP?. Using these mice, we show that megakaryocyte/erythroid progenitors (MEPs) and common lymphoid progenitors (CLPs) could be redirected to functional macrophages in vitro by a short-term activation of C/EBP?, and the conversion occurred clonally through biphenotypic intermediate cells. Moreover, in vivo activation of C/EBP? in mice led to the increase of mature granulocytes and myeloid progenitors with a concomitant decrease of hematopoietic stem cells and nonmyeloid progenitors. Our study reveals that C/EBP? can activate the latent myeloid differentiation program of MEP and CLP and shows that its global activation affects multilineage homeostasis in vivo.

Fukuchi, Yumi; Shibata, Fumi; Ito, Miyuki; Goto-Koshino, Yuko; Sotomaru, Yusuke; Ito, Mamoru; Kitamura, Toshio; Nakajima, Hideaki

2006-01-01

184

Spleens of myelofibrosis patients contain malignant hematopoietic stem cells  

PubMed Central

Cancer stem cell behavior is thought to be largely determined by intrinsic properties and by regulatory signals provided by the microenvironment. Myelofibrosis (MF) is characterized by hematopoiesis occurring not only in the marrow but also in extramedullary sites such as the spleen. In order to study the effects of these different microenvironments on primitive malignant hematopoietic cells, we phenotypically and functionally characterized splenic and peripheral blood (PB) MF CD34+ cells from patients with MF. MF spleens contained greater numbers of malignant primitive HPCs than PB. Transplantation of PB MF CD34+ cells into immunodeficient (NOD/SCID/IL2R?null) mice resulted in a limited degree of donor cell chimerism and a differentiation program skewed toward myeloid lineages. By contrast, transplanted splenic MF CD34+ cells achieved a higher level of chimerism and generated both myeloid and lymphoid cells that contained molecular or cytogenetic abnormalities indicating their malignant nature. Only splenic MF CD34+ cells were able to sustain hematopoiesis for prolonged periods (9 months) and were able to engraft secondary recipients. These data document the existence of MF stem cells (MF-SCs) that reside in the spleens of MF patients and demonstrate that these MF-SCs retain a differentiation program identical to that of normal hematopoietic stem cells.

Wang, Xiaoli; Prakash, Sonam; Lu, Min; Tripodi, Joseph; Ye, Fei; Najfeld, Vesna; Li, Yan; Schwartz, Myron; Weinberg, Rona; Roda, Paul; Orazi, Attilio; Hoffman, Ronald

2012-01-01

185

IL12B expression is sustained by a heterogenous population of myeloid lineages during tuberculosis.  

PubMed

IL12B is required for resistance to Mycobacterium tuberculosis (Mtb) infection, promoting the initiation and maintenance of Mtb-specific effector responses. While this makes the IL12-pathway an attractive target for experimental tuberculosis (TB) therapies, data regarding what lineages express IL12B after infection is established are limited. This is not obvious in the lung, an organ in which both hematopoietic and non-hematopoietic lineages produce IL12p40 upon pathogen encounter. Here, we use radiation bone marrow chimeras and Yet40 reporter mice to determine what lineages produce IL12p40 during experimental TB. We observed that hematopoietic IL12p40-production was sufficient to control Mtb, with no contribution by non-hematopoietic lineages. Furthermore, rather than being produced by a single subset, IL12p40 was produced by cells that were heterogenous in their size, granularity, autofluorescence and expression of CD11c, CD11b and CD8?. While depending on the timepoint and tissue examined, the surface phenotype of IL12p40-producers most closely resembled macrophages based on previous surveys of lung myeloid lineages. Importantly, depletion of CD11c(hi) cells during infection had no affect on lung IL12p40-concentrations. Collectively, our data demonstrate that IL12p40 production is sustained by a heterogenous population of myeloid lineages during experimental TB, and that redundant mechanisms of IL12p40-production exist when CD11c(hi) lineages are absent. PMID:23491716

Reeme, Allison E; Miller, Halli E; Robinson, Richard T

2013-03-13

186

Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation  

PubMed Central

Background The clinical use of chromatin-modulating drugs, such as histone deacetylase inhibitors, for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last few years. Nonetheless, little is currently known concerning their effects on myelopoiesis. Design and Methods We utilized an ex vivo differentiation system in which umbilical cord blood-derived CD34+ cells were treated with trichostatin A, sodium butyrate and valproic acid to evaluate the effect of histone deacetylase inhibitor treatment on myeloid lineage development, colony-forming potential, proliferation, and terminal neutrophil differentiation. Results Trichostatin A treatment modestly reduced progenitor proliferation, while sodium butyrate and valproic acid resulted in concentration-dependent effects on proliferation and apoptosis. Addition of valproic acid uniquely stimulated CD34+ proliferation. Sodium butyrate treatment inhibited terminal neutrophil differentiation both quantitatively and qualitatively. Addition of 100 ?M valproic acid resulted in increased numbers of mature neutrophils with a block in differentiation at increasing concentrations. Sodium butyrate and valproic acid treatment resulted in increased acetylation of histones 3 and 4 while trichostatin A, sodium butyrate and valproic acid had differential effects on the acetylation of non-histone proteins. Conclusions Individual histone deacetylase inihibitors had specific effects on cell fate decisions during myeloid development. These data provide novel insights into the effects of histone deacetylase inhibitors on the regulation of normal hematopoiesis, which is of importance when considering utilizing these compounds for the treatment of myeloid malignancies and bone marrow failure syndromes.

Bartels, Marije; Geest, Christian R.; Bierings, Marc; Buitenhuis, Miranda; Coffer, Paul J.

2010-01-01

187

Primary Myeloid Sarcoma Masquerading as an Obstructing Duodenal Carcinoma  

PubMed Central

Myeloid Sarcoma (MS), a rare extra hematopoietic carcinoma composed of blast cells, is located primarily in extramedullary sites such as skin, soft tissue, lymph nodes, and bone. MS usually presents in the setting of coexisting acute myeloid leukemia (AML) and myeloproliferative disorders. Gastrointestinal involvement (GI) is extremely rare from nonspecific abdominal symptoms to obstruction. Eight cases of myeloid sarcoma involving the duodenum including the current case have been reported, overall mean age being 40 years (range 17–71) and M?:?F ratio 7?:?1. The prognosis of patients with de novo MS cases has been reported to be better than those who have a coexisting leukemia. MS is a rare extramedullary tumor, which should be considered in the differential diagnosis of a soft tissue mass involving the duodenum, especially if there is a coexisting hematological disorder. De novo cases often progress to AML, and current therapy involves Daunorubicin- and Cytarabine-based chemotherapy. The wide cytogenetic and molecular heterogeneity of MS implies a potential role for more targeted MS therapies, which may offer a curative strategy.

Narayan, Preeti; Murthy, Vijayashree; Su, Mu; Woel, Rosemonde; Grossman, I. Robert; Chamberlain, Ronald S.

2012-01-01

188

Zebrafish model for allogeneic hematopoietic cell transplantation not requiring preconditioning  

PubMed Central

Recent work on vertebrate hematopoiesis has uncovered the presence of deeply rooted similarities between fish and mammals at molecular and cellular levels. Although small animal models such as zebrafish are ideally suited for genetic and chemical screens, the study of cellular aspects of hematopoietic development in lower vertebrates is severely hampered by the complex nature of their histocompatibility-determining genes. Hence, even when hosts are sublethally irradiated before hematopoietic cell transplantation, stable and long-term reconstitution by allogeneic stem cells often fails. Here, we describe the unexpected observation that transplantation and maintenance of allogeneic hematopoietic stem cells in zebrafish homozygous for the c-mybt25127 allele, carrying a missense mutation (Ile181Asn) in the DNA binding domain can be achieved without prior conditioning. Using this model, we examined several critical parameters of zebrafish hematopoiesis in a near-physiological setting. Limiting dilution analysis suggests that the kidney marrow of adult zebrafish harbors about 10 transplantable hematopoietic stem cells; this tissue also contains thymus-settling precursors that colonize the thymic rudiment within days after transplantation and initiate robust T-cell development. We also demonstrate that c-myb mutants can be stably reconstituted with hematopoietic cells carrying specific genetic defects in lymphocyte development, exemplifying one of the many potential uses of this model in experimental hematology.

Hess, Isabell; Iwanami, Norimasa; Schorpp, Michael; Boehm, Thomas

2013-01-01

189

Nras(G12D/+) promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions.  

PubMed

Oncogenic NRAS mutations are frequently identified in human myeloid leukemias. In mice, expression of endogenous oncogenic Nras (Nras(G12D/+)) in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and a chronic myeloproliferative neoplasm (MPN). However, acute expression of Nras(G12D/+) in a pure C57BL/6 background does not induce hyperactivated granulocyte macrophage colony-stimulating factor signaling or increased proliferation in myeloid progenitors. It is thus unclear how Nras(G12D/+) signaling promotes leukemogenesis. Here, we show that hematopoietic stem cells (HSCs) expressing Nras(G12D/+) serve as MPN-initiating cells. They undergo moderate hyperproliferation with increased self-renewal. The aberrant Nras(G12D/+) HSC function is associated with hyperactivation of ERK1/2 in HSCs. Conversely, downregulation of MEK/ERK by pharmacologic and genetic approaches attenuates the cycling of Nras(G12D/+) HSCs and prevents the expansion of Nras(G12D/+) HSCs and myeloid progenitors. Our data delineate critical mechanisms of oncogenic Nras signaling in HSC function and leukemogenesis. PMID:23687087

Wang, Jinyong; Kong, Guangyao; Liu, Yangang; Du, Juan; Chang, Yuan-I; Tey, Sin Ruow; Zhang, Xinmin; Ranheim, Erik A; Saba-El-Leil, Marc K; Meloche, Sylvain; Damnernsawad, Alisa; Zhang, Jingfang; Zhang, Jing

2013-05-17

190

¹?F MRI tracer preserves in vitro and in vivo properties of hematopoietic stem cells.  

PubMed

Hematopoietic stem cells (HSCs) have numerous therapeutic applications including immune reconstitution, enzyme replacement, regenerative medicine, and immunomodulation. The trafficking and persistence of these cells after administration is a fundamental question for future therapeutic applications of HSCs. Here, we describe the safe and efficacious labeling of human CD34(+) HSCs with a novel, self-delivering perfluorocarbon ¹?F magnetic resonance imaging (MRI) tracer, which has recently been authorized for use in a clinical trial to track therapeutic cells. While various imaging contrast agents have been used to track cellular therapeutics, the impact of this MRI tracer on HSC function has not previously been studied. Both human CD34(+) and murine bone marrow (BM) HSCs were effectively labeled with the MRI tracer, with only a slight reduction in viability, relative to mock-labeled cells. In a pilot study, ¹?F MRI enabled the rapid evaluation of HSC delivery/retention following administration into a rat thigh muscle, revealing the dispersal of HSCs after injection, but not after surgical implantation. To investigate effects on cell functionality, labeled and unlabeled human HSCs were tested in in vitro colony forming unit (CFU) assays, which resulted in equal numbers of total CFU as well as individual CFU types, indicating that labeling did not alter multipotency. Cobblestone assay forming cell precursor frequency was also unaffected, providing additional evidence that stem cell function was preserved after labeling. In vivo tests of multipotency and reconstitution studies in mice with murine BM containing labeled HSCs resulted in normal development of CFU in the spleen, compared to unlabeled cells, and reconstitution of both lymphoid and myeloid compartments. The lack of interference in these complex biological processes provides strong evidence that the function and therapeutic potential of the HSCs are likely maintained after labeling. These data support the safety and efficacy of the MRI tracer for clinical tracking of human stem cells. PMID:22862925

Helfer, Brooke M; Balducci, Anthony; Sadeghi, Zhina; O'Hanlon, Charles; Hijaz, Adonis; Flask, Chris A; Wesa, Amy

2012-08-02

191

Transfusion-Associated Iron Overload as an Adverse Risk Factor for Transplantation Outcome in Patients Undergoing Reduced-Intensity Stem Cell Transplantation for Myeloid Malignancies  

Microsoft Academic Search

Transfusion-associated iron overload could be an important risk factor in myeloablative hematopoietic stem cell transplantation. However, few studies have evaluated the effect of iron overload in reduced-intensity stem cell transplantation (RIST). We evaluated 38 patients with myeloid malignancies, 16 with and 22 without iron overload, who received RIST. We used pretransplant serum ferritin as a marker of iron overload. There

Yu Ri Kim; Jin Seok Kim; June-Won Cheong; Jae Woo Song; Yoo Hong Min

2008-01-01

192

FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model  

Microsoft Academic Search

FLT3 receptor tyrosine kinase is ex- pressed on lymphoid and myeloid pro- genitors in the hematopoietic system. Ac- tivating mutations in FLT3 have been identified in approximately 30% of pa- tients with acute myelogenous leukemia, making it one of the most common muta- tions observed in this disease. Frequently, the mutation is an in-frame internal tan- dem duplication (ITD) in

Louise M. Kelly; Qing Liu; Jeffrey L. Kutok; Ifor R. Williams; Christina L. Boulton; D. Gary

193

Bone marrow derived mesenchymal stem cells from chronic myeloid leukemia t(9;22) patients are devoid of Philadelphia chromosome and support cord blood stem cell expansion  

Microsoft Academic Search

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. It is characterized at cytogenetic level by the Philadelphia (Ph) chromosome and at the molecular level by the BCR\\/ABL gene rearrangement. Bone marrow derived mesenchymal stem cells (MSCs) are also pluripotent stem cells that can differentiate into several mesenchymal tissues. To date, no study has been performed

Saengsuree Jootar; Nida Pornprasertsud; Sawang Petvises; Busaba Rerkamnuaychoke; Sinee Disthabanchong; Samart Pakakasama; Artit Ungkanont; Suradej Hongeng

2006-01-01

194

Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD\\/SCID engrafting potential  

Microsoft Academic Search

Aldehyde dehydrogenase (ALDH) activity is used to define normal hematopoietic stem cell (HSC), but its link to leukemic stem cells (LSC) in acute myeloid leukemia (AML) is currently unknown. We hypothesize that ALDH activity in AML might be correlated with the presence of LSC. Fifty-eight bone marrow (BM) samples were collected from AML (n=43), acute lymphoblastic leukemia (ALL) (n=8) and

A M S Cheung; T S K Wan; J C K Leung; L Y Y Chan; H Huang; Y L Kwong; R Liang; A Y H Leung; AYH Leung

2007-01-01

195

Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI.  

PubMed

One unique feature of vertebrate definitive hematopoiesis is the ontogenic switching of hematopoietic stem cells from one anatomical compartment or niche to another. In mice, hematopoietic stem cells are believed to originate in the aorta-gonad-mesonephros (AGM), subsequently migrate to the fetal liver (FL) and finally colonize the bone marrow (BM). Yet, the differentiation potential of hematopoietic stem cells within early niches such as the AGM and FL remains incompletely defined. Here, we present in vivo analysis to delineate the differentiation potential of definitive hematopoietic stem/progenitor cells (HSPCs) in the zebrafish AGM and FL analogies, namely the ventral wall of dorsal aorta (VDA) and the posterior blood island (PBI), respectively. Cell fate mapping and analysis of zebrafish runx1(w84x) and vlad tepes (vlt(m651)) mutants revealed that HSPCs in the PBI gave rise to both erythroid and myeloid lineages. However, we surprisingly found that HSPCs in the VDA were not quiescent but were uniquely adapted to generate myeloid but not erythroid lineage cells. We further showed that such distinct differentiation output of HSPCs was, at least in part, ascribed to the different micro-environments present in these two niches. Our results highlight the importance of niche in shaping the differentiation output of developing HSPCs. PMID:19168679

Jin, Hao; Sood, Raman; Xu, Jin; Zhen, Fenghua; English, Milton A; Liu, P Paul; Wen, Zilong

2009-02-01

196

The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone.  

PubMed

Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6(+/+) and IL-6(-/-) mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6(-/-) compared with IL-6(+/+) bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6(-/-) earlier than IL-6(+/+) marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6(-/-) marrow. In the skeletal system, although intermittent PTH administration to IL-6(+/+) and IL-6(-/-) mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-?1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system. PMID:23297399

Cho, Sun Wook; Pirih, Flavia Q; Koh, Amy J; Michalski, Megan; Eber, Matthew R; Ritchie, Kathryn; Sinder, Benjamin; Oh, Seojin; Al-Dujaili, Saja A; Lee, JoonHo; Kozloff, Ken; Danciu, Theodora; Wronski, Thomas J; McCauley, Laurie K

2013-01-07

197

Use of chromosome engineering to model a segmental deletion of chromosome band 7q22 found in myeloid malignancies.  

PubMed

Monosomy 7 and del(7q) are associated with adverse features in myeloid malignancies. A 2.5-Mb commonly deleted segment (CDS) of chromosome band 7q22 is implicated as harboring a myeloid tumor suppressor gene (TSG); however, molecular analysis of candidate TSGs has not uncovered loss of function. To determine whether haploinsufficiency for the 7q22 CDS contributes to myeloid leukemogenesis, we performed sequential gene targeting to flank a region of orthologous synteny on mouse chromosome band 5A3 with loxP sites. We then generated Mx1-Cre, 5A3(fl) mutant mice and deleted the targeted interval in vivo. Although excision was inefficient, we confirmed somatic deletion of the 5A3 CDS in the hematopoietic stem cell compartment. Mx1-Cre, 5A3(fl) mice show normal hematologic parameters and do not spontaneously develop myeloid malignancies. The 5A3(fl) deletion does not cooperate with oncogenic Kras(G12D) expression, Nf1 inactivation, or retroviral mutagenesis to accelerate leukemia development and did not modulate responsiveness to antileukemia drugs. These studies demonstrate that it is feasible to somatically delete a large chromosomal segment implicated in tumor suppression in hematopoietic cell populations in vivo; however, our data do not support the hypothesis that the 7q22/5A3 CDS interval contains a myeloid TSG. PMID:20233966

Wong, Jasmine C Y; Zhang, Yan; Lieuw, Kenneth H; Tran, Mary T; Forgo, Erna; Weinfurtner, Kelley; Alzamora, Pilar; Kogan, Scott C; Akagi, Keiko; Wolff, Linda; Le Beau, Michelle M; Killeen, Nigel; Shannon, Kevin

2010-03-16

198

Omega 3 fatty acids reduce myeloid progenitor cell frequency in the bone marrow of mice and promote progenitor cell differentiation  

PubMed Central

Background Omega 3 fatty acids have been found to inhibit proliferation, induce apoptosis, and promote differentiation in various cell types. The processes of cell survival, expansion, and differentiation are of key importance in the regulation of hematopoiesis. We investigated the role of omega 3 fatty acids in controlling the frequency of various myeloid progenitor cells in the bone marrow of mice. Increased progenitor cell frequency and blocked differentiation are characteristics of hematopoietic disorders of the myeloid lineage, such as myeloproliferative diseases and myeloid leukemias. Results We found that increasing the proportion of omega 3 fatty acids relative to the proportion of omega 6 fatty acids in the diet caused increased differentiation and reduced the frequency of myeloid progenitor cells in the bone marrow of mice. Furthermore, this had no adverse effect on peripheral white blood cell counts. Conclusion Our results indicate that omega 3 fatty acids impact hematopoietic differentiation by reducing myeloid progenitor cell frequency in the bone marrow and promoting progenitor cell differentiation. Further exploration of this discovery could lead to the use of omega 3 fatty acids as a therapeutic option for patients that have various disorders of hematopoiesis.

Varney, Melinda E; Hardman, W Elaine; Sollars, Vincent E

2009-01-01

199

SCL/TAL1 regulates hematopoietic specification from human embryonic stem cells.  

PubMed

Determining the molecular regulators/pathways responsible for the specification of human embryonic stem cells (hESCs) into hematopoietic precursors has far-reaching implications for potential cell therapies and disease modeling. Mouse models lacking SCL/TAL1 (stem cell leukemia/T-cell acute lymphocytic leukemia 1) do not survive beyond early embryogenesis because of complete absence of hematopoiesis, indicating that SCL is a master early hematopoietic regulator. SCL is commonly found rearranged in human leukemias. However, there is barely information on the role of SCL on human embryonic hematopoietic development. Differentiation and sorting assays show that endogenous SCL expression parallels hematopoietic specification of hESCs and that SCL is specifically expressed in hematoendothelial progenitors (CD45(-)CD31(+)CD34(+)) and, to a lesser extent, on CD45(+) hematopoietic cells. Enforced expression of SCL in hESCs accelerates the emergence of hematoendothelial progenitors and robustly promotes subsequent differentiation into primitive (CD34(+)CD45(+)) and total (CD45(+)) blood cells with higher clonogenic potential. Short-hairpin RNA-based silencing of endogenous SCL abrogates hematopoietic specification of hESCs, confirming the early hematopoiesis-promoting effect of SCL. Unfortunately, SCL expression on its own is not sufficient to confer in vivo engraftment to hESC-derived hematopoietic cells, suggesting that additional yet undefined master regulators are required to orchestrate the stepwise hematopoietic developmental process leading to the generation of definitive in vivo functional hematopoiesis from hESCs. PMID:22491213

Real, Pedro J; Ligero, Gertrudis; Ayllon, Veronica; Ramos-Mejia, Veronica; Bueno, Clara; Gutierrez-Aranda, Ivan; Navarro-Montero, Oscar; Lako, Majlinda; Menendez, Pablo

2012-04-10

200

SCL/TAL1 Regulates Hematopoietic Specification From Human Embryonic Stem Cells  

PubMed Central

Determining the molecular regulators/pathways responsible for the specification of human embryonic stem cells (hESCs) into hematopoietic precursors has far-reaching implications for potential cell therapies and disease modeling. Mouse models lacking SCL/TAL1 (stem cell leukemia/T-cell acute lymphocytic leukemia 1) do not survive beyond early embryogenesis because of complete absence of hematopoiesis, indicating that SCL is a master early hematopoietic regulator. SCL is commonly found rearranged in human leukemias. However, there is barely information on the role of SCL on human embryonic hematopoietic development. Differentiation and sorting assays show that endogenous SCL expression parallels hematopoietic specification of hESCs and that SCL is specifically expressed in hematoendothelial progenitors (CD45?CD31+CD34+) and, to a lesser extent, on CD45+ hematopoietic cells. Enforced expression of SCL in hESCs accelerates the emergence of hematoendothelial progenitors and robustly promotes subsequent differentiation into primitive (CD34+CD45+) and total (CD45+) blood cells with higher clonogenic potential. Short-hairpin RNA–based silencing of endogenous SCL abrogates hematopoietic specification of hESCs, confirming the early hematopoiesis-promoting effect of SCL. Unfortunately, SCL expression on its own is not sufficient to confer in vivo engraftment to hESC-derived hematopoietic cells, suggesting that additional yet undefined master regulators are required to orchestrate the stepwise hematopoietic developmental process leading to the generation of definitive in vivo functional hematopoiesis from hESCs.

Real, Pedro J; Ligero, Gertrudis; Ayllon, Veronica; Ramos-Mejia, Veronica; Bueno, Clara; Gutierrez-Aranda, Ivan; Navarro-Montero, Oscar; Lako, Majlinda; Menendez, Pablo

2012-01-01

201

Myeloid derived suppressor cells  

PubMed Central

The goal of achieving measurable response with cancer immunotherapy requires counteracting the immunosuppressive characteristics of tumors. One of the mechanisms that tumors utilize to escape immunosurveillance is the activation of myeloid derived suppressor cells (MDSCs). Upon activation by tumor-derived signals, MDSCs inhibit the ability of the host to mount an anti-tumor immune response via their capacity to suppress both the innate and adaptive immune systems. Despite their relatively recent discovery and characterization, anti-MDSC agents have been identified, which may improve immunotherapy efficacy.

Waldron, Todd J.; Quatromoni, Jon G.; Karakasheva, Tatiana A.; Singhal, Sunil; Rustgi, Anil K.

2013-01-01

202

Mobilized Human CD34 Hematopoietic Stem Cells Enhance Tumor Growth in a Nonobese Diabetic\\/Severe Combined Immunodeficient Mouse Model of Human Non-Hodgkin's Lymphoma1  

Microsoft Academic Search

Autologous peripheral blood stem cell mobilization is increasingly ap- plied in the treatment of hematological malignancies. Despite the frequent clinical use in a setting of residual disease, it is not known whether mobilization of hematopoietic stem cells might facilitate tumor outgrowth in vivo. In the bone marrow, a bipotential precursor for hematopoietic and endothelial cells called hemangioblast exists. This hemangioblast,

Jeroen E. J. Guikema; Frank Scherpen; Tiny Meeuwsen; Willem A. Kamps; Edo Vellenga; Nico A. Bos

2001-01-01

203

Splenectomy in myeloid metaplasia.  

PubMed Central

A retrospective review of 19 patients with documented myeloid metaplasia undergoing, elective splenectomy during the past ten years at the Peter Bent Brigham Hospital is presented. The primary indications for splenectomy in 17 of these 19 were either hypersplenism or symptomatic splenomegaly. Eighteen of the 19 underwent both 59Fe-ferrokinetic studies and 51Cr-sequestration studies or, alternatively, 111In-marrow scintigraphy as a part of their routine preoperative evaluation. The death from sepsis of one patient six weeks post-operatively, whose marrow function was poor and whose level of splenic sequestration was minimal, confirms the efficacy of these studies in the preoperative prediction of hematologic response to splenectomy. Eighteen of the 19 patients benefited from the operation in terms of symptomatic relief and/or hematologic improvement, although surgery presumably did nothing to prolong survival in these patients. We conclude that splenectomy is indicated as a palliative maneuver for carefully selected patients with myeloid metaplasia without prohibitive operative risk, provided the criteria for selection of patients are adhered to and the surgeon and hematologist work together as a team.

Cabot, E B; Brennan, M F; Rosenthal, D S; Wilson, R E

1978-01-01

204

Generation of Hematopoietic Colony-Forming Cells From Embryonic Stem Cells: Synergy Between a Soluble Factor From NIH-3T3 Cells and Hematopoietic Growth Factors  

Microsoft Academic Search

Murine embryonic stem cells are able to differentiate into embryoid bodies (EBs) in vitro in the absence of leukemia- inhibitory factor with the formation of different types of he- matopoietic precursors within these EBs. With the aim of determining the in vitro requirements for the continued de- velopment of hematopoietic colony-forming cells (CFCs) and their progeny from embryonic stem-derived cells,

A. Bigas; D. I. K. Martin; I. D. Bernstein

1995-01-01

205

Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia  

PubMed Central

There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ?60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ? 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway. This study is registered at www.clinicaltrials.gov as # NCT00890929.

Pollyea, Daniel A.; Zehnder, James; Coutre, Steve; Gotlib, Jason R.; Gallegos, Leonel; Abdel-Wahab, Omar; Greenberg, Peter; Zhang, Bing; Liedtke, Michaela; Berube, Caroline; Levine, Ross; Mitchell, Beverly S.; Medeiros, Bruno C.

2013-01-01

206

Interferon -2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia  

Microsoft Academic Search

Background: Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration. Patients and methods: We studied the efficacy and tolerability

P. Mollee; C. Arthur; T. Hughes; H. Januszewicz; A. Grigg; K. Bradstock; M. Wolf; J. Gibson; A. P. Schwarer; A. Spencer; P. Browett; T. Hawkins; M. Seldon; R. Herrmann; A. Watson; J. F. Seymour; N. Martin; S. Shina; S. Wright; R. Rodwell; J. Coulston; J. Morton; H. Blacklock; D. Taylor; K. M. Taylor

2004-01-01

207

Hematopoietic Precursor Cells Transiently Reestablish Permissiveness for X Inactivation  

Microsoft Academic Search

Xist is the trigger for X inactivation in female mammals. The long noncoding Xist RNA localizes along one of the two female X chromosomes and initiates chromosome-wide silencing in the early embryo. In differen- tiated cells, Xist becomes dispensable for the maintenance of the inactive X, and its function for initiation of silencing is lost. How Xist mediates gene repression

Fabio Savarese; Katja Flahndorfer; Rudolf Jaenisch; Meinrad Busslinger; Anton Wutz

2006-01-01

208

Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling.  

PubMed

Previous studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show no overt hematopoietic abnormalities. We now demonstrate that Hes is required for the development of HSC in the mouse embryo, a function previously undetected as the result of functional compensation by de novo expression of Hes5 in the aorta/gonad/mesonephros (AGM) region of Hes1 mutants. Analysis of embryos deficient for Hes1 and Hes5 reveals an intact arterial program with overproduction of nonfunctional hematopoietic precursors and total absence of HSC activity. These alterations were associated with increased expression of the hematopoietic regulators Runx1, c-myb, and the previously identified Notch target Gata2. By analyzing the Gata2 locus, we have identified functional RBPJ-binding sites, which mutation results in loss of Gata2 reporter expression in transgenic embryos, and functional Hes-binding sites, which mutation leads to specific Gata2 up-regulation in the hematopoietic precursors. Together, our findings show that Notch activation in the AGM triggers Gata2 and Hes1 transcription, and next HES-1 protein represses Gata2, creating an incoherent feed-forward loop required to restrict Gata2 expression in the emerging HSCs. PMID:23267012

Guiu, Jordi; Shimizu, Ritsuko; D'Altri, Teresa; Fraser, Stuart T; Hatakeyama, Jun; Bresnick, Emery H; Kageyama, Ryoichiro; Dzierzak, Elaine; Yamamoto, Masayuki; Espinosa, Lluis; Bigas, Anna

2012-12-24

209

Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling  

PubMed Central

Previous studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show no overt hematopoietic abnormalities. We now demonstrate that Hes is required for the development of HSC in the mouse embryo, a function previously undetected as the result of functional compensation by de novo expression of Hes5 in the aorta/gonad/mesonephros (AGM) region of Hes1 mutants. Analysis of embryos deficient for Hes1 and Hes5 reveals an intact arterial program with overproduction of nonfunctional hematopoietic precursors and total absence of HSC activity. These alterations were associated with increased expression of the hematopoietic regulators Runx1, c-myb, and the previously identified Notch target Gata2. By analyzing the Gata2 locus, we have identified functional RBPJ-binding sites, which mutation results in loss of Gata2 reporter expression in transgenic embryos, and functional Hes-binding sites, which mutation leads to specific Gata2 up-regulation in the hematopoietic precursors. Together, our findings show that Notch activation in the AGM triggers Gata2 and Hes1 transcription, and next HES-1 protein represses Gata2, creating an incoherent feed-forward loop required to restrict Gata2 expression in the emerging HSCs.

Guiu, Jordi; Shimizu, Ritsuko; D'Altri, Teresa; Fraser, Stuart T.; Hatakeyama, Jun; Bresnick, Emery H.; Kageyama, Ryoichiro; Dzierzak, Elaine; Yamamoto, Masayuki; Espinosa, Lluis

2013-01-01

210

Hematopoietic stimulation by porphyrin photosensitizers (Invited Paper)  

NASA Astrophysics Data System (ADS)

The effects of the photosensitizers, PhotofrinTM and benozoporphyrin derivative monoacid ring A (BPD) on a variety of hematopoietic cell functions have been studied, both in the presence and absence of light activation. A marked increase in hematopoiesis was observed in the bone marrow and spleens of DBA/2 mice administered high dose Photofrin but not BPD. This was manifested in an increased relative spleen weight, nucleated spleen cell number and circulating white blood cell concentration 7 days following Photofrin injection. We have shown that BPD and light doses just below phototoxic ranges stimulate the growth of human colony forming committed myeloid progenitors as well as pluripotent stem cells grown in long term marrow culture. Studies on the effect of BPD on the function of T lymphocytes in the absence of light has also demonstrated a stimulatory effect. The dose range in which this is observed is considerably broader than that observed with light activation. The mechanisms involved in this stimulatory effect have been studied and are discussed.

Levy, Julia G.; Hunt, David W.; Mitchell, David W.; Jamieson, Catriona H.

1992-06-01

211

Chronic Myeloid Leukaemia  

PubMed Central

Chronic myeloid leukaemia (CML), previously a fatal illness, is now readily manageable with oral medication. First described in the 1840s, there was no widely accepted cure until the advent of allogeneic stem cell transplantation in the late 1970s. This treatment was of limited value because of donor availability and toxicity problems. Discovering the Philadelphia chromosome and demonstrating that the BCR-ABL chimaeric gene was responsible for the malignant phenotype opened new avenues. The development of tyrosine kinase inhibitors (TKIs) changed the lives of patients with CML. The treatment has been so successful that compliance is now a problem. Currently under discussion is the possible use of more expensive second generation TKIs for newly diagnosed patients. In spite of the success with TKIs, treatment of common cancers has not been so successful. Is CML therefore a paradigm for malignancy or just a strange disease?

McCann, Shaun R.

2012-01-01

212

Curing chronic myeloid leukemia.  

PubMed

The use of tyrosine kinase inhibitors (TKIs) targeted against the BCR-ABL1 oncoprotein has proven remarkably successful in chronic myeloid leukemia (CML) and long-term survival has become a reality. Despite this outstanding progress, detection of minimal residual disease precludes therapy termination in most TKI-receiving patients. CML has thus turned into a chronic illness, raising concerns about long-term safety, medication adherence, and health care costs. Although treatment cessation may be feasible in few selected patients achieving deep molecular responses, a definitive cure remains elusive owing to the discovery that TKIs spare quiescent leukemic stem cells (LSC). Understanding mechanisms underlying LSC behavior in TKI-treated patients may provide important clues to develop an array of strategies that ensure the complete destruction of LSC reservoirs and thereby offer CML patients a definitive cure. PMID:22410764

Rea, Delphine; Rousselot, Philippe; Guilhot, Joelle; Guilhot, François; Mahon, François-Xavier

2012-06-01

213

Recombinant factor VIII expression in hematopoietic cells following lentiviral transduction.  

PubMed

Autologous transplantation of gene-modified hematopoietic stem cells may provide a therapeutic strategy for several monogeneic disorders. In previous studies, retroviral gene transfer of coagulation factor VIII (FVIII) into FVIII(-/-) mouse bone marrow (BM) cells did not result in detectable plasma FVIII levels. However, specific immune tolerance was achieved against neo-antigenic FVIII. Here, we used lentiviral vectors to study the ability of various hematopoietic cell types to synthesize and secrete recombinant FVIII. Several myeloid, monocytic and megakaryocytic cell lines (K-562, TF-1, Monomac-1, Mutz-3, Meg-01) expressed FVIII at 2-12 mU/10(4) cells. In contrast, two lymphatic cell lines, BV-173 and Molt-4, were less-efficiently transduced and did not express detectable FVIII. Similarly, peripheral blood-derived primary monocytes were transduced efficiently and expressed up to 20 mU/10(4) cells, whereas primary lymphocytes did not express FVIII. Although human and canine CD34(+) cells were transduced efficiently, the cells expressed very low levels of FVIII (up to 0.8 mU/10(4) cells). Following xenotransplantation of transduced CD34(+) into NOD/SCID mice, ELISA failed to detect FVIII in the plasma of engrafted mice. However, NOD/SCID repopulating cell (SRC)-derived human monocytes isolated from BM of these mice secreted functional recombinant FVIII after culture ex vivo. Again, SRC-derived human lymphocytes did not secrete FVIII. Therefore, certain hematopoietic cell types are able to synthesize and secrete functional recombinant FVIII. Our results show for the first time that transplantation of transduced CD34(+) progenitors may give rise to differentiated hematopoietic cells secreting a nonhematopoietic recombinant protein. PMID:14502221

Tiede, A; Eder, M; von Depka, M; Battmer, K; Luther, S; Kiem, H-P; Ganser, A; Scherr, M

2003-10-01

214

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: evidence for premature aging of the myeloid compartment.  

PubMed

Telomere shortening, a well-known marker of aging and cellular stress, occurs under several conditions in the hematopoietic compartment, including aplastic anemia and following iatrogenic noxae. We decided to verify whether pathological telomere erosion also arises in restored Philadelphia-negative (Ph-negative) hematopoiesis following successful treatment of chronic myeloid leukemia (CML). Eighty-one CML patients in complete cytogenetic remission were compared to 76 age-matched healthy subjects. Myeloid cells of CML patients had shorter telomeres than controls (6521 bp vs 7233 bp, p<0.001). This difference was specific for the myeloid compartment, since it was not observed in lymphoid cells (6774 bp vs 6909 bp, p=0.620). Acquired Ph-negative cytogenetic abnormalities (p=0.010), lack of complete molecular remission (p=0.016) and age (p=0.013) were independent predictors of telomere shortening. Telomere dynamics were assessed over a median follow-up period of 22 months. We documented accelerated non-physiological ongoing telomere shortening in 17/59 CML patients (28%). Patients experiencing grade 2-4 hematological toxicity, during CML remission possessed significantly shorter telomeres compared to those lacking toxicity (p=0.005 for any toxicity, p=0.007 for anemia). CML patients suffer from significant and often ongoing telomere stress resulting in premature and selective aging of the myeloid compartment which might have long-term consequences on function and integrity of Ph-negative hematopoiesis. PMID:22687638

Lobetti-Bodoni, Chiara; Ferrero, Dario; Genuardi, Elisa; Passera, Roberto; Bernocco, Elisa; Sia, Daniela; Grignani, Giovanni; Crisà, Elena; Monitillo, Luigia; Rocci, Alberto; Drandi, Daniela; Giai, Valentina; Zanni, Manuela; Boi, Michela; Isaia, Gianluca; Barbero, Daniela; Lunghi, Monia; Abruzzese, Elisabetta; Radaelli, Franca; Pini, Massimo; Pregno, Patrizia; Carlo-Stella, Carmelo; Gaidano, Gianluca; Boccadoro, Mario; Ladetto, Marco

2012-06-09

215

Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress  

PubMed Central

Hematopoietic stem cells (HSCs) possess long-term self-renewal capacity and multipotent differentiative capacity, to maintain the hematopoietic system. Long-term hematopoietic homeostasis requires effective control of genotoxic damage to maintain HSC function and prevent propagation of deleterious mutations. Here we investigate the role of the BH3-only Bcl-2 family member Bid in the response of murine hematopoietic cells to long-term replicative stress induced by hydroxyurea (HU). The PI3-like serine/threonine kinase, ATR, initiates the DNA damage response (DDR) to replicative stress. The pro-apoptotic Bcl-2 family member, Bid, facilitates this response to replicative stress in hematopoietic cells, but the in vivo role of this DDR function of Bid has not been defined. Surprisingly, we demonstrate that long-term HU treatment expands wild-type myeloid progenitor cells (MPCs) and HSC-enriched Lin?Sca1+Kit+ (LSK) cells to maintain bone marrow function as measured by long-term competitive repopulating ability. Bid?/? MPCs demonstrate increased sensitivity to HU and are depleted. Bid?/? LSK cells demonstrate increased mobilization manifest by increased Bromodeoxyuridine (BrdU) incorporation. Bid?/? MPCs and LSK cells are relatively depleted, however, and bone marrow from Bid?/? mice demonstrates decreased long-term competitive repopulating ability in both primary and secondary transplants. We thus describe a survival function of Bid in hematopoiesis in the setting of chronic replicative stress.

Liu, Y; Aiello, A; Zinkel, S S

2012-01-01

216

LAPTM5: A novel lysosomal-associated multispanning membrane protein preferentially expressed in hematopoietic cells  

SciTech Connect

While a large body of knowledge about cell membrane proteins exists, much less is known about the repertoire and function of integral membrane proteins of intracellular organelles. In looking for novel classes of genes that are functionally important to hematopoietic cells, we have cloned the cDNA for a gene preferentially expressed in adult hematopoietic tissues. During embryonic development the gene is expressed in both hematopoietic and nonhematopoietic tissues. In cell lines the gene is expressed specifically in hematopoietic lineages, whereas in normal adult tissues the mRNA is preferentially detected at high levels in lymphoid and myeloid tissues. The predicted protein is a pentaspanner with no homology to known genes and conserved across evolution. Immunocytological and cell fractionation studies with a specific antibody revealed a protein localizing in lysosomes. The gene, provisionally named LAPTM5, maps to chromosome 1p34. The expression pattern of the gene together with preliminary evidence that the protein interacts with ubiquitin indicates that the protein may have a special functional role during embryogenesis and in adult hematopoietic cells. 53 refs., 9 figs.

Adra, C.N.; Zhu, Shaochun; Ko, Jone-Long [Harvard Medical School, Boston, MA (United States)] [and others

1996-07-15

217

An In Vivo Functional Screen Uncovers miR-150-Mediated Regulation of Hematopoietic Injury Response  

PubMed Central

Summary Hematopoietic stem and progenitor cells are often undesired targets of chemotherapies, leading to hematopoietic suppression requiring careful clinical management. Whether microRNAs control hematopoietic-injury response is largely unknown. We report a novel in vivo gain-of-function screen and identification of miR-150 as an inhibitor of hematopoietic recovery upon 5-fluorouracil-induced injury. Utilizing a bone marrow transplant model with a barcoded microRNA-library, we screened for barcode abundance in peripheral blood of recipient mice before and after 5-fluorouracil treatment. Overexpression of screen-candidate miR-150 resulted in significantly slowed recovery rates across major blood lineages, with associated impairment of bone marrow clonogenic potential. Conversely, platelets and myeloid cells from miR-150-null marrow recovered faster after 5-fluorouracil treatment. Heterozygous knockout of c-myb, a conserved target of miR-150, partially phenocopied miR-150 forced expression. Our data highlight the role of microRNAs in controlling hematopoietic-injury response, and demonstrate the power of in vivo functional screens for studying microRNAs in normal tissue physiology.

Adams, Brian D.; Guo, Shangqin; Bai, Haitao; Guo, Yanwen; Megyola, Cynthia; Cheng, Jijun; Heydari, Kartoosh; Xiao, Changchun; Reddy, E. Premkumar; Lu, Jun

2012-01-01

218

PXD101 in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2013-06-03

219

CYTOLOGICAL EVIDENCE FOR A RELATIONSHIP BETWEEN NORMAL HEMATOPOIETIC COLONY-FORMING CELLS AND CELLS OF THE LYMPHOID SYSTEM  

PubMed Central

The relationship between hematopoietic colony-forming stem cells and cells in the thymus and lymph nodes of unirradiated mice has been investigated using a chromosome-marker technique. It was found that a high proportion of cells in the thymus may belong to the same clone as normal hematopoietic colony-forming cells. It was also found that cells belonging to the same clone as colony-forming cells may reach the lymph nodes, and that nodes containing such cells can participate in an immunological response against sheep red cells. Either the precursors of cells in thymus and lymph node are identical with hematopoietic colony-forming cells, or they are both descendants of a common precursor which has not yet been identified. The results are compatible with the view that cells of the hematopoietic system and the immune system may be derived from the same stem cell.

Wu, A. M.; Till, J. E.; Siminovitch, L.; McCulloch, E. A.

1968-01-01

220

Cyclophosphamide treatment expands the circulating hematopoietic stem cell pool in dogs.  

PubMed Central

Increased numbers of circulating granulocyte-monocyte precursor cells (CFUc) have been observed in the peripheral blood of man after antineoplastic chemotherapy. We have developed a canine model to study the biologic significance of this phenomenon for hematopoietic reconstitution following hematopoietically lethal exposure to total body irradiation (TBI). After cyclophosphamide administration, a 16-fold expansion of circulating CFUc numbers was observed during the period of rapid leukocyte recovery that occurred after the chemotherapy-induced leukocyte nadir. We had previously noted this association between leukocyte recovery and CFUc expansion in our human studies. After 900 rad TBI hematopoietic reconstitution was attempted with autologous, cryopreserved collections of peripheral blood mononuclear cells obtained either at times of post-cyclophosphamide CFUc expansion (group A, 14 dogs) or without CFUc expansion (group B, 12 dogs). Asd compared to group B collections, group A collections contained 11-fold more CFUc and were 12.5-fold more potent in fostering hematopoietic recovery after TBI. These results suggest that the expansion of CFUc numbers we observed was accompanied by a similar expansion of more primitive hematopoietic stem cell numbers. We conclude that chemotherapy-induced expansion of circulating CFUc numbers appears to be of substantial import in effecting hematopoietic reconstitution--an observation that may be of significance for further studies of autologous hematopoietic reconstitution in man.

Abrams, R A; McCormack, K; Bowles, C; Deisseroth, A B

1981-01-01

221

The origin and evolution of mutations in Acute Myeloid Leukemia  

PubMed Central

Summary Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability, driving clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of AML samples with a known initiating event (PML-RARA) vs. normal karyotype AML samples, and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.

Welch, John S.; Ley, Timothy J.; Link, Daniel C.; Miller, Christopher A.; Larson, David E.; Koboldt, Daniel C.; Wartman, Lukas D.; Lamprecht, Tamara L.; Liu, Fulu; Xia, Jun; Kandoth, Cyriac; Fulton, Robert S.; McLellan, Michael D.; Dooling, David J.; Wallis, John W.; Chen, Ken; Harris, Christopher C.; Schmidt, Heather K.; Kalicki-Veizer, Joelle M.; Lu, Charles; Zhang, Qunyuan; Lin, Ling; O'Laughlin, Michelle D.; McMichael, Joshua F.; Delehaunty, Kim D.; Fulton, Lucinda A.; Magrini, Vincent J.; McGrath, Sean D.; Demeter, Ryan T.; Vickery, Tammi L.; Hundal, Jasreet; Cook, Lisa L.; Swift, Gary W.; Reed, Jerry P.; Alldredge, Patricia A.; Wylie, Todd N.; Walker, Jason R.; Watson, Mark A.; Heath, Sharon E.; Shannon, William D.; Varghese, Nobish; Nagarajan, Rakesh; Payton, Jacqueline E.; Baty, Jack D.; Kulkarni, Shashikant; Klco, Jeffery M.; Tomasson, Michael H.; Westervelt, Peter; Walter, Matthew J.; Graubert, Timothy A.; DiPersio, John F.; Ding, Li; Mardis, Elaine R.; Wilson, Richard K.

2012-01-01

222

Occupational exposure to formaldehyde, hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells  

PubMed Central

There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing and other industries. Epidemiological studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on formaldehyde’s ability to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse impact on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures.

Zhang, Luoping; Tang, Xiaojiang; Rothman, Nathaniel; Vermeulen, Roel; Ji, Zhiying; Shen, Min; Qiu, Chuangyi; Guo, Weihong; Liu, Songwang; Reiss, Boris; Laura Beane, Freeman; Ge, Yichen; Hubbard, Alan E.; Hua, Ming; Blair, Aaron; Galvan, Noe; Ruan, Xiaolin; Alter, Blanche P.; Xin, Kerry X.; Li, Senhua; Moore, Lee E.; Kim, Sungkyoon; Xie, Yuxuan; Hayes, Richard B.; Azuma, Mariko; Hauptmann, Michael; Xiong, Jun; Stewart, Patricia; Li, Laiyu; Rappaport, Stephen M.; Huang, Hanlin; Fraumeni, Joseph F.; Smith, Martyn T.; Lan, Qing

2010-01-01

223

Hematopoietic progenitor cells from allogeneic bone marrow transplant donors circulate in the very early post-transplant period  

Microsoft Academic Search

Despite the therapeutic efficacy of allogeneic bone marrow transplantation (allo-BMT), circulating hematopoietic progenitor cells after bone marrow transplantation have not been well characterized. In the present study, we focused on these ‘post-transplant circulating progenitor cells (PTCPC)’ which may be on their way to bone marrow. We analyzed the number of myeloid progenitor cells (CFU-GM) per 10 ml of peripheral blood

Y Katayama; N Mahmut; H Takimoto; Y Maeda; T Yano; K Kojima; T Azuma; M Hara; K Imajyo; S Takahashi; T Kai; Y Ohno; T Miyamoto; K Nagafuji; K Matsue; K Takenaka; T Teshima; K Shinagawa; F Ishimaru; E Omoto; M Harada

1999-01-01

224

Excision of Ets by an inducible site-specific recombinase causes differentiation of Myb–Ets-transformed hematopoietic progenitors  

Microsoft Academic Search

Background: The Myb–Ets protein encoded by the E26 acute avian leukemia virus is a paradigm for the function of fused transcriptional activator oncoproteins. Myb–Ets transforms hematopoietic progenitor cells (Myb–Ets progenitors, MEPs) that can be induced to differentiate into eosinophilic and myeloid cells by the activation of pathways involving Ras and\\/or protein kinase C. The Ets portion of the fusion protein

Fabio Rossi; Kelly M McNagny; Colin Logie; A. Francis Stewart; Thomas Graf

1996-01-01

225

NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells  

Microsoft Academic Search

NUP98-HOXA9, the chimeric protein resulting from the t(7;11)(p15;p15) chromosomal translocation, is a prototype of several NUP98 fusions that occur in myelodysplastic syndromes and acute myeloid leukemia. We examined its effect on differentiation, proliferation, and gene expression in primary human CD34+ hematopoietic cells. Colony-forming cell (CFC) assays in semisolid medium combined with morphologic examination and flow cytometric immunophe- notyping revealed that

Akiko Takeda; Charles Goolsby; Nabeel R. Yaseen

2006-01-01

226

Bcr-Abl is a “Molecular Switch” for the Decision for Growth and Differentiation in Hematopoietic Stem Cells  

Microsoft Academic Search

Chronic myeloid leukemia (CML) is a clonal disorder originating in the pluripotent hematopoietic stem cell (HSC), the hallmark\\u000a of which is the constitutively activated p210-type of Bcr-Abl tyrosine kinase protein. Studies in recent years have helped\\u000a us to understand the molecular processes involved in the initiation and progression of CML. Although a great amount of knowledge\\u000a has been accumulated, the

Takumi Era

2002-01-01

227

IL12 Gene Therapy of Leukemia with Hematopoietic Progenitor Cells without the Toxicity of Systemic IL12 Treatment  

Microsoft Academic Search

We have previously shown that the myeloid progenitor cell line 32Dc13 transduced with mIL-12 cDNAs (32DIL-12 cells) induces IFN-? and NK-cell-mediated cytotoxicity in vivo. Since systemic therapy with recombinant IL-12 protein has been shown to produce moderate to severe toxic side effects we examined whether IL-12 gene therapy with hematopoietic progenitor cells also induces systemic toxicities that are commonly associated

Yong X. Xu; Xiaohua Gao; Nalini Janakiraman; Robert A. Chapman; Subhash C. Gautam

2001-01-01

228

Genetic modification of hematopoietic stem cells: recent advances in the gene therapy of inherited diseases  

Microsoft Academic Search

Hematopoietic stem cells constitute a rare population of precursor cells with remarkable properties for being used as targets in gene therapy protocols. The last years have been particularly productive both in the fields of gene therapy and stem cell biology. Results from ongoing clinical trials have shown the first unquestionable clinical benefits of immunodeficient patients transplanted with genetically modified autologous

Juan A Bueren; Guillermo Guenechea; José A Casado; Mar??a Luisa Lamana; José C Segovia

2003-01-01

229

Myeloid Lineage of Human Endothelial Outgrowth Cells Circulating in Blood and Vasculogenic Endothelial-Like Cells in the Diseased Vessel Wall  

Microsoft Academic Search

Endothelial injury is a major step in the pathogenesis of atherosclerosis. Accumulated data suggest endothelial progenitor cells can derive from various sources, including the host bone marrow, circulating blood mononuclear cells, as well as resident precursors within the vessel wall. Early experimental animal data supported a haematopoietic origin for vascular precursors, but more recently cells of myeloid lineage have been

Chunsheng Liu; Shaohua Wang; Pat Metharom; Noel M. Caplice

2009-01-01

230

Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages  

PubMed Central

During carcinogenesis, tumors induce dysfunctional development of hematopoietic cells. Myeloid lineage cells, in the form of myeloid derived suppressor cells (MDSCs) and alternatively polarized M2 macrophages, influence almost all types of cancers by regulating diverse facets of immunosuppression, angiogenesis, cell proliferation, growth and metastasis. One-third of Americans are obese, and accumulating evidence suggests that obesity is a risk factor for various cancers. However, the relationship between these immune players and obesity are not well-described. In this review, we evaluate potential mechanisms through which different aspects of obesity, namely insulin resistance, increased estrogen, adiposity and low grade chronic inflammation from adipose tissue macrophages, may coalesce to promote MDSC induction and M2 macrophage polarization, thereby facilitating cancer development. Detailed understanding of the interplay between obesity and myeloid mediated immunosuppression may provide novel avenues for therapeutic targeting, with the goal to reduce the challenge obesity presents towards gains made in cancer outcomes.

Okwan-Duodu, Derick; Umpierrez, Guillermo E; Brawley, Otis W; Diaz, Roberto

2013-01-01

231

Repression of Id2 expression by Gfi-1 is required for B-cell and myeloid development  

PubMed Central

The development of mature blood cells from hematopoietic stem cells requires coordinated activities of transcriptional networks. Transcriptional repressor growth factor independence 1 (Gfi-1) is required for the development of B cells, T cells, neutrophils, and for the maintenance of hematopoietic stem cell function. However, the mechanisms by which Gfi-1 regulates hematopoiesis and how Gfi-1 integrates into transcriptional networks remain unclear. Here, we provide evidence that Id2 is a transcriptional target of Gfi-1, and repression of Id2 by Gfi-1 is required for B-cell and myeloid development. Gfi-1 binds to 3 conserved regions in the Id2 promoter and represses Id2 promoter activity in transient reporter assays. Increased Id2 expression was observed in multipotent progenitors, myeloid progenitors, T-cell progenitors, and B-cell progenitors in Gfi-1?/? mice. Knockdown of Id2 expression or heterozygosity at the Id2 locus partially rescues the B-cell and myeloid development but not the T-cell development in Gfi-1?/? mice. These studies demonstrate a role of Id2 in mediating Gfi-1 functions in B-cell and myeloid development and provide a direct link between Gfi-1 and the B-cell transcriptional network by its ability to repress Id2 expression.

Li, Huajie; Ji, Ming; Klarmann, Kimberly D.

2010-01-01

232

Major remodelling of the murine stem cell kinome following differentiation in the hematopoietic compartment  

PubMed Central

The changes in signal transduction associated with the acquisition of specific cell fates remain poorly understood. We performed massive parallel assessment of kinase signatures of the radiations of the hematopoietic system, including long-term repopulating hematopoietic stem cells (LT-HSC), short-term repopulating HSC (ST-HSC), immature natural killer (iNK) cells, NK cells, B cells, T cells and myeloid cells. The LT-HSC kinome is characterised by non-canonical Wnt, Ca2+ and classical protein kinase C (PKC)-driven signalling, which is lost upon the transition to ST-HSC, whose kinome signature prominently features receptor tyrosine kinase (RTK) activation of the Ras/MAPK signalling cassette. Further differentiation to iNK maintains signalling through this cassette but simultaneously leads to activation of a PI3K/PKB/Rac signalling, which becomes the dominant trait in the kinase signature following full differentiation towards NK cells. Differentiation along the myeloid and B cell lineages is accompanied by hyperactivation of both the Ras/MAPK and PI3K/PKB/Rac signalling cassette. T cells, however, deactivate signalling and only display residual G protein-coupled pathways. Thus, differentiation along the hematopoietic lineage is associated with major remodelling of cellular kinase signature.

Hazen, Amy L.; Diks, Sander H.; Wahle, Joseph A.; Fuhler, Gwenny M.; Peppelenbosch, Maikel P.; Kerr, William G.

2011-01-01

233

RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia  

PubMed Central

Background Criteria for good candidate antigens for immunotherapy of acute myeloid leukemia are high expression on leukemic stem cells in the majority of patients with acute myeloid leukemia and low or no expression in vital tissues. It was shown in vaccination trials that Receptor for Hyaluronic Acid Mediated Motility (RHAMM/HMMR) generates cellular immune responses in patients with acute myeloid leukemia and that these responses correlate with clinical benefit. It is not clear however whether this response actually targets the leukemic stem cell, especially since it was reported that RHAMM is expressed maximally during the G2/M phase of the cell cycle. In addition, tumor specificity of RHAMM expression remains relatively unexplored. Design and Methods Blood, leukapheresis and bone marrow samples were collected from both acute myeloid leukemia patients and healthy controls. RHAMM expression was assessed at protein and mRNA levels on various sorted populations, either fresh or after manipulation. Results High levels of RHAMM were expressed by CD34+CD38+ and CD34- acute myeloid leukemia blasts. However, only baseline expression of RHAMM was measured in CD34+CD38- leukemic stem cells, and was not different from that in CD34+CD38- hematopoietic stem cells from healthy controls. RHAMM was significantly up-regulated in CD34+ cells from healthy donors during in vitro expansion and during in vivo engraftment. Finally, we demonstrated an explicit increase in the expression level of RHAMM after in vitro activation of T cells. Conclusions RHAMM does not fulfill the criteria of an ideal target antigen for immunotherapy of acute myeloid leukemia. RHAMM expression in leukemic stem cells does not differ significantly from the expression in hematopoietic stem cells from healthy controls. RHAMM expression in proliferating CD34+ cells of healthy donors and activated T cells further compromises RHAMM-specific T-cell-mediated immunotherapy.

Snauwaert, Sylvia; Vanhee, Stijn; Goetgeluk, Glenn; Verstichel, Greet; Van Caeneghem, Yasmine; Velghe, Imke; Philippe, Jan; Berneman, Zwi N.; Plum, Jean; Taghon, Tom; Leclercq, Georges; Thielemans, Kris; Kerre, Tessa; Vandekerckhove, Bart

2012-01-01

234

Myeloid leukemia after hematotoxins  

SciTech Connect

One of the most serious consequences of cancer therapy is the development of a second cancer, especially leukemia. Several distinct subsets of therapy-related leukemia can now be distinguished. Classic therapy-related myeloid leukemia typically occurs 5 to 7 years after exposure to alkylating agents and/or irradiation, has a myelodysplastic phase with trilineage involvement, and is characterized by abnormalities of the long arms of chromosomes 5 and/or 7. Response to treatment is poor, and allogeneic bone marrow transplantation is recommended. Leukemia following treatment with agents that inhibit topoisomerase 11, however, has a shorter latency, no preleukemic phase, a monoblastic, myelomonocytic, or myeloblastic phenotype, and balanced translocations, most commonly involving chromosome bands 11 q23 or 21 q22. The MLL gene at 11 q23 or the AML1 gene at 21 q22 are almost uniformly rearranged. MLL is involved with many fusion gene partners. Therapy-related acute lymphoblastic leukemia also occurs with 1 1 q23 rearrangements. Therapy-related leukemias with 11 q23 or 21 q22 rearrangements, inv(16) or t(15;17), have a more favorable response to treatment and a clinical course similar to their de novo counterparts. 32 refs., 4 tabs.

Larson, R.A.; LeBeau, M.M.; Vardiman, J.W.; Rowley, J.D. [Univ. of Chicago, IL (United States)

1996-12-01

235

Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors  

PubMed Central

Nonviral conversion of skin or blood cells into clinically useful human induced pluripotent stem cells (hiPSC) occurs in only rare fractions (?0.001%–0.5%) of donor cells transfected with non-integrating reprogramming factors. Pluripotency induction of developmentally immature stem-progenitors is generally more efficient than differentiated somatic cell targets. However, the nature of augmented progenitor reprogramming remains obscure, and its potential has not been fully explored for improving the extremely slow pace of non-integrated reprogramming. Here, we report highly optimized four-factor reprogramming of lineage-committed cord blood (CB) myeloid progenitors with bulk efficiencies of ?50% in purified episome-expressing cells. Lineage-committed CD33+CD45+CD34? myeloid cells and not primitive hematopoietic stem-progenitors were the main targets of a rapid and nearly complete non-integrated reprogramming. The efficient conversion of mature myeloid populations into NANOG+TRA-1-81+ hiPSC was mediated by synergies between hematopoietic growth factor (GF), stromal activation signals, and episomal Yamanaka factor expression. Using a modular bioinformatics approach, we demonstrated that efficient myeloid reprogramming correlated not to increased proliferation or endogenous Core factor expressions, but to poised expression of GF-activated transcriptional circuits that commonly regulate plasticity in both hematopoietic progenitors and embryonic stem cells (ESC). Factor-driven conversion of myeloid progenitors to a high-fidelity pluripotent state was further accelerated by soluble and contact-dependent stromal signals that included an implied and unexpected role for Toll receptor-NF?B signaling. These data provide a paradigm for understanding the augmented reprogramming capacity of somatic progenitors, and reveal that efficient induced pluripotency in other cell types may also require extrinsic activation of a molecular framework that commonly regulates self-renewal and differentiation in both hematopoietic progenitors and ESC.

Park, Tea Soon; Huo, Jeffrey S.; Peters, Ann; Talbot, C. Conover; Verma, Karan; Zimmerlin, Ludovic; Kaplan, Ian M.; Zambidis, Elias T.

2012-01-01

236

Novel Variant Ph Translocation t(9;22;11)(q34;q11.2;p15)inv(9)(p13q34) in Chronic Myeloid Leukemia Involving a One-Step Mechanism  

Microsoft Academic Search

Chronic myeloid leukemia (CML) is a clonal malignant disorder of a pluripotent hematopoietic stem cell characterized by the presence of a Philadelphia (Ph) chromosome. Less than 10% of patients present variant Ph chromosomes involving 1 or more additional chromosomes, other than chromosomes 9 and 22, with uncertain prognosis. There are mainly 1- or 2-step mechanisms proposed to explain the genesis

C. Belli; M. F. Alú; G. Alfonso; M. Bianchini; I. Larripa

2011-01-01

237

Axl expression is associated with adverse prognosis and with expression of Bcl2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK)  

Microsoft Academic Search

Receptor tyrosine kinases (RTK) play a significant role in the signal transduction of normal, and malignant hematopoietic cells. We have previously shown that Axl, a novel RTK, is mainly expressed in leukemias of myeloid origin, and that its expression may be associated with cells of monocytic origin. Since expression of certain RTKs in cancer may be associated with different biology

C Rochlitz; A Lohri; M Bacchi; M Schmidt; S Nagel; M Fopp; MF Fey; R Herrmann; A Neubauer

1999-01-01

238

Dasatinib in chronic myeloid leukemia: a review  

PubMed Central

Deregulated BCR-ABL tyrosine kinase (TK) activity is the molecular marker for chronic myeloid leukemia (CML), which provides an identifiable target for developing therapeutic agents. Imatinib mesylate, a BCR-ABL TK inhibitor, is the frontline therapy for CML. Despite the stunning efficacy of this agent, a small number of patients develop a suboptimal response or resistance to imatinib. In newly diagnosed patients with chronic phase CML, the rate of resistance to imatinib at 4 years was up to 20%, increasing to 70% to 90% for patients in the accelerated/blastic phase. Resistance to imatinib led to the development of novel TK inhibitors such as dasatinib. Several clinical trials have reported more durable complete hematologic and cytogenetic responses with this agent in patients who are resistant or intolerant to imatinib. Dasatinib is well tolerated and has broad efficacy, resulting in durable responses in patients with any BCR-ABL mutation except for T3151 and mutations in codon 317 – most commonly F317L – including mutations that were highly resistant to imatinib, such as L248, Y253, E255, F359, and H396. Dasatinib is recommended for CML in chronic, blastic or accelerated phase that is resistant or intolerant to imatinib. Dasatinib was approved by the FDA at 100 mg once daily as the starting dose in patients with chronic phase CML and at 70 mg twice daily in patients with accelerated or blastic phase CML. Various clinical trial results provided evidence that resistance to one TK inhibitor can be reversed with the use of a different TK inhibitor (TKI). Other second-generation TKIs with activity in CML include nilotinib, bosutinib and INNO 406. New molecules, such as the inhibitor of Aurora family serine-threonine kinases, MK0457, which has antileukemic activity in CML associated with a T315I mutation, are being investigated. Allogeneic hematopoietic stem cell transplantation remains an option for selected patients.

Aguilera, Dolly G; Tsimberidou, Apostolia M

2009-01-01

239

Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.  

PubMed

Stem cell factor (SCF) is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1) in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1? accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1? accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH)-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1? prolyl hydroxylase (PHD) activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1? accumulation is controlled via ERK, PI3 kinase/PKC-?/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle. PMID:21799876

Gibbs, Bernhard F; Yasinska, Inna M; Oniku, Abraham E; Sumbayev, Vadim V

2011-07-20

240

C/EBP? deregulation results in differentiation arrest in acute myeloid leukemia  

PubMed Central

C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBP? is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBP? hypermethylation/silencing. Similarly, C/EBP? was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBP?, as C/EBP? mediates C/EBP? suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBP?-C/EBP? balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBP? mediates the myeloid differentiation arrest induced by C/EBP? deficiency and that targeting the C/EBP?-C/EBP? axis rescues neutrophilic differentiation in this unique subset of AMLs.

Alberich-Jorda, Meritxell; Wouters, Bas; Balastik, Martin; Shapiro-Koss, Clara; Zhang, Hong; DiRuscio, Annalisa; Radomska, Hanna S.; Ebralidze, Alexander K.; Amabile, Giovanni; Ye, Min; Zhang, Junyan; Lowers, Irene; Avellino, Roberto; Melnick, Ari; Figueroa, Maria E.; Valk, Peter J.M.; Delwel, Ruud; Tenen, Daniel G.

2012-01-01

241

Prognosis of patients with core binding factor acute myeloid leukemia after first relapse  

PubMed Central

Core binding factor acute myeloid leukemia is known to have a favorable prognosis, however, there have been no detailed analyses on prognostic factors after first relapse. Using a nationwide database, we retrospectively analyzed core binding factor acute myeloid leukemia patients who relapsed after being treated with chemotherapy alone during their first complete remission. Of a total of 397 patients who were diagnosed with core binding factor acute myeloid leukemia, 208 experienced a first relapse, and analyses were performed in 139 patients for whom additional data were available. In the entire cohort, the overall survival rate after relapse was 48% at 3 years. By multivariate analysis, younger age at diagnosis, a longer interval before relapse, and inv(16) were shown to be independently associated with better survival after relapse. Although there was no significant difference in survival after relapse between patients who underwent allogeneic hematopoietic cell transplantation and those who did not in the overall series of relapsed patients, we found that transplantation significantly improved survival among patients who had t(8;21) (54% versus 26% at 3 years, P=0.002). In addition, among patients with t(8;21), those who had different cytogenetics at relapse had a significantly improved survival after transplantation, while those who had same cytogenetics did not. We showed that the prognosis differs significantly and optimal treatment strategies may vary between groups of patients with core binding factor acute myeloid leukemia with different cytogenetic profiles at relapse. These findings may help to guide therapeutic decisions after first relapse.

Kurosawa, Saiko; Miyawaki, Shuichi; Yamaguchi, Takuhiro; Kanamori, Heiwa; Sakura, Toru; Moriuchi, Yukiyoshi; Sano, Fumiaki; Kobayashi, Takeshi; Yasumoto, Atsushi; Hatanaka, Kazuo; Yanada, Masamitsu; Nawa, Yuichiro; Takeuchi, Jin; Nakamura, Yukinori; Fujisawa, Shin; Shibayama, Hirohiko; Miura, Ikuo; Fukuda, Takahiro

2013-01-01

242

H2.0-like homeobox (HLX) regulates early hematopoiesis and promotes acute myeloid leukemia  

PubMed Central

Summary Homeobox domain-containing transcription factors are important regulators of hematopoiesis. Here we report that increased levels of non-clustered H2.0-like homeobox (HLX) lead to loss of functional hematopoietic stem cells and formation of aberrant progenitors with unlimited serial clonogenicity and blocked differentiation. Inhibition of HLX reduces proliferation and clonogenicity of leukemia cells, overcomes the differentiation block, and leads to prolonged survival. HLX regulates a transcriptional program, including PAK1 and BTG1, that controls cellular differentiation and proliferation. HLX is overexpressed in 87% of patients with acute myeloid leukemia (AML) and independently correlates with inferior overall survival (N=601, p=2.3×10?6). Our study identifies HLX as a key regulator in immature hematopoietic and leukemia cells, and a prognostic marker and therapeutic target in AML.

Kawahara, Masahiro; Pandolfi, Ashley; Bartholdy, Boris; Barreyro, Laura; Will, Britta; Roth, Michael; Okoye-Okafor, Ujunwa C.; Todorova, Tihomira I.; Figueroa, Maria E.; Melnick, Ari; Mitsiades, Constantine S.; Steidl, Ulrich

2012-01-01

243

Hematopoietic stem cell transplantation in China: current status and prospects  

PubMed Central

During the past four decades, a substantial progress has been made in the field of hematopoietic stem cell transplantation (HSCT). From July, 2007 to December, 2010, a transplant survey from 42 HSCT units indicates that the types of transplantation performed are related identical (43%), related mismatched/haploidentical (28%), unrelated donor matched (11%), unrelated donor mismatched (7%), umbilical cord blood (UCB, 2%) and autologous (9%). The distribution of disease entities being transplanted in allogeneic settings is acute myeloid leukemia (AML) (34%), acute lymphoblastic leukemia(ALL) (24%), chronic myeloid leukemia (CML) (20%), myelodysplastic syndrome (MDS) (8%), aplastic anemia (AA) (7%), Mediterranean anemia (MIA) (2%), non-Hodgkin's lymphoma (NHL) (3%), and other diseases (3%). Clinical data from Peking University Institute of Hematology and other transplant centers suggest that haploidentical transplantation has been a choice of the best alternative source of stem cells for individual patients without matched sibling donors. A modified donor lymphocyte infusion (DLI) approach can be safely used for prophylaxis and treatment of leukemia relapse in patients with advanced leukemia following mismatched transplant. The number of transplants from unrelated donor or related mismatched/haploidentical donor has increased significantly during recent years. Double UCBT is a promising strategy for the therapy of hematological disease. In addition, mesenchymal stem cell (MSC) transplantation may be a potential therapeutic approach for treating systemic lupus erythematosus (SLE).

Huang, Xiao-Jun

2011-01-01

244

Hematopoietic stem cell transplantation in China: current status and prospects.  

PubMed

During the past four decades, a substantial progress has been made in the field of hematopoietic stem cell transplantation (HSCT). From July, 2007 to December, 2010, a transplant survey from 42 HSCT units indicates that the types of transplantation performed are related identical (43%), related mismatched/haploidentical (28%), unrelated donor matched (11%), unrelated donor mismatched (7%), umbilical cord blood (UCB, 2%) and autologous (9%). The distribution of disease entities being transplanted in allogeneic settings is acute myeloid leukemia (AML) (34%), acute lymphoblastic leukemia(ALL) (24%), chronic myeloid leukemia (CML) (20%), myelodysplastic syndrome (MDS) (8%), aplastic anemia (AA) (7%), Mediterranean anemia (MIA) (2%), non-Hodgkin's lymphoma (NHL) (3%), and other diseases (3%). Clinical data from Peking University Institute of Hematology and other transplant centers suggest that haploidentical transplantation has been a choice of the best alternative source of stem cells for individual patients without matched sibling donors. A modified donor lymphocyte infusion (DLI) approach can be safely used for prophylaxis and treatment of leukemia relapse in patients with advanced leukemia following mismatched transplant. The number of transplants from unrelated donor or related mismatched/haploidentical donor has increased significantly during recent years. Double UCBT is a promising strategy for the therapy of hematological disease. In addition, mesenchymal stem cell (MSC) transplantation may be a potential therapeutic approach for treating systemic lupus erythematosus (SLE). PMID:22432069

Huang, Xiao-Jun

2011-06-01

245

Gemtuzumab Ozogamicin in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

2013-09-23

246

Colony forming cell assays for human hematopoietic progenitor cells.  

PubMed

Hematopoietic stem cells (HSCs) present in small numbers in adult bone marrow (BM), peripheral blood (PB) and umbilical cord blood (CB) produce a heterogeneous pool of progenitors that can be detected in vitro using colony forming cell (CFC) assays. Hematopoietic progenitor cells proliferate and differentiate to produce colonies of maturing cells when cultured in a semisolid methylcellulose-based medium that is supplemented with suitable growth factors and other supplements. The colonies are then classified and enumerated in situ by light microscopy or an automated imaging instrument. CFC assays are important tools in basic hematology research but are also used by clinical cell processing laboratories to measure the progenitor cell content of BM, CB and mobilized PB (MPB) preparations used for cell transplantation. Standard CFC assays for human progenitor cells require a culture period of at least 14 days to enable optimal outgrowth and differentiation of the maximum number of CFCs in a cell preparation. In this chapter protocols are described for the detection and enumeration of myeloid multipotential progenitors and committed progenitors of the erythroid, monocyte, and granulocyte lineages in samples from human PB, MPB, BM, and CB. In addition protocols are described for a modified version of the CFC-assay that allows accurate enumeration of total CFC numbers in CB or MPB after a culture period of only 7 days, but without distinction of colony types. PMID:23179838

Wognum, Bert; Yuan, Ning; Lai, Becky; Miller, Cindy L

2013-01-01

247

Arrayed lentiviral barcoding for quantification analysis of hematopoietic dynamics.  

PubMed

Our understanding of system dynamics of mixed cell populations in whole organisms has benefited from the advent of individual cell marking by non-arrayed DNA barcodes subsequently analyzed by high-throughput DNA sequencing. However, key limitations include statistical biases compromising quantification and the lack of applicability to deconvolute individual cell fate in vivo after pooling single cells differentially exposed to different conditions ex vivo. Here, we have derived an arrayed lentiviral library of DNA barcodes and obtained a proof-of-concept of its resolving capacity by quantifying hematopoietic regeneration after engraftment of mice with genetically modified autologous cells. This method has helped clarify and bridge the seemingly opposed clonal-succession and continuous-recruitment models of hematopoietic stem cell behavior and revealed that myeloid-lymphoid biases are common occurrences in steady-state hematopoiesis. Arrayed lentiviral barcoding should prove a versatile and powerful approach to deconvolute cell dynamics in vivo with applications in hematology, embryology and cancer biology. PMID:23554255

Grosselin, Jeanne; Sii-Felice, Karine; Payen, Emmanuel; Chretien, Stany; Roux, Diana Tronik-Le; Leboulch, Philippe

2013-04-01

248

On the origin of hematopoietic stem cells: progress and controversy.  

PubMed

Hematopoietic Stem Cells (HSCs) are responsible for the production and replenishment of all blood cell types during the entire life of an organism. Generated during embryonic development, HSCs transit through different anatomical niches where they will expand before colonizing in the bone marrow, where they will reside during adult life. Although the existence of HSCs has been known for more than fifty years and despite extensive research performed in different animal models, there is still uncertainty with respect to the precise origins of HSCs. We review the current knowledge on embryonic hematopoiesis and highlight the remaining questions regarding the anatomical and cellular identities of HSC precursors. PMID:22099016

Boisset, Jean-Charles; Robin, Catherine

2011-07-30

249

Hypoxia and HIFs in regulating the development of the hematopoietic system.  

PubMed

Many physiologic processes during the early stages of mammalian ontogeny, particularly placental and vascular development, take place in the low oxygen environment of the uterus. Organogenesis is affected by hypoxia inducible factor (HIF) transcription factors that are sensors of hypoxia. In response to hypoxia, HIFs activate downstream target genes - growth and metabolism factors. During hematopoietic system ontogeny, blood cells and hematopoietic progenitor/stem cells are respectively generated from mesodermal precursors, hemangioblasts, and from a specialized subset of endothelial cells that are hemogenic. Since HIFs are known to play a central role in vascular development, and hematopoietic system development occurs in parallel to that of the vascular system, several studies have examined the role of HIFs in hematopoietic development. The response to hypoxia has been examined in early and mid-gestation mouse embryos through genetic deletion of HIF subunits. We review here the data showing that hematopoietic tissues of the embryo are hypoxic and express HIFs and HIF downstream targets, and that HIFs regulate the development and function of hematopoietic progenitor/stem cells. PMID:24103835

Imanirad, Parisa; Dzierzak, Elaine

2013-10-05

250

CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential.  

PubMed

A unique subset of CD86(-) HSCs was previously discovered in mice that were old or chronically stimulated with lipopolysaccharide. Functionally defective HSCs were also present in those animals, and we now show that CD86(-) CD150(+) CD48(-) HSCs from normal adult mice are particularly poor at restoring the adaptive immune system. Levels of the marker are high on all progenitors with lymphopoietic potential, and progressive loss helps to establish relations between progenitors corresponding to myeloid and erythroid lineages. CD86 represents an important tool for subdividing HSCs in several circumstances, identifying those unlikely to generate a full spectrum of hematopoietic cells. PMID:22371880

Shimazu, Tomoyuki; Iida, Ryuji; Zhang, Qingzhao; Welner, Robert S; Medina, Kay L; Alberola-Lla, José; Kincade, Paul W

2012-02-27

251

Evaluation of hematopoietic potential generated by transplantation of muscle-derived stem cells in mice.  

PubMed

Muscle tissue of adult mice has been shown to contain stem cells with hematopoietic repopulation ability in vivo. To determine the functional characteristics of stem cells giving rise to this hematopoietic activity, we have performed hematopoietic reconstitution experiments by the use of muscle versus marrow transplantation in lethally irradiated mice and followed the fate of transplanted cells by Y-chimerism using PCR and fluorescence in situ hybridization (FISH) analysis. We report here that transplantation of murine muscle generate a major hematopoietic chimerism at the level of CFU-C, CFU-S, and terminally-differentiated cells in three generations of lethally irradiated mice followed up to 1 year after transplantation. This potential is totally abolished when muscle grafts were performed by the use of muscle from previously irradiated mice. As compared to marrow transplantation, muscle transplants were able to generate similar potencies to give rise to myeloid, T, B, and natural killer (NK) cells. Interestingly, marrow stem cells that have been generated in primary and then in secondary recipients were able to contribute efficiently to myofibers in the muscle tissue of tertiary recipients. Altogether, our data demonstrate that muscle-derived stem cells present a major hematopoietic repopulating ability with evidence of self-replication in vivo. They are radiation-sensitive and similar to marrow-derived stem cells in terms of their ability to generate multilineage hematopoiesis. Finally, our data demonstrate that muscle-derived hematopoietic stem cells do not lose their ability to contribute to myofiber generation after at least two rounds of serial transplantation, suggesting a potential that is probably equivalent to that generated by marrow transplantation. PMID:15068696

Farace, Francoise; Prestoz, Laetitita; Badaoui, Sabrina; Guillier, Martine; Haond, Celine; Opolon, Paule; Thomas, Jean-Leon; Zalc, Bernard; Vainchenker, William; Turhan, Ali G

2004-02-01

252

Biochemical correction of X-CGD by a novel chimeric promoter regulating high levels of transgene expression in myeloid cells.  

PubMed

X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency caused by mutations in the CYBB gene encoding the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase catalytic subunit gp91(phox). A recent clinical trial for X-CGD using a spleen focus-forming virus (SFFV)-based ?-retroviral vector has demonstrated clear therapeutic benefits in several patients although complicated by enhancer-mediated mutagenesis and diminution of effectiveness over time due to silencing of the viral long terminal repeat (LTR). To improve safety and efficacy, we have designed a lentiviral vector that directs transgene expression primarily in myeloid cells. To this end, we created a synthetic chimeric promoter that contains binding sites for myeloid transcription factors CAAT box enhancer-binding family proteins (C/EBPs) and PU.1, which are highly expressed during granulocytic differentiation. As predicted, the chimeric promoter regulated higher reporter gene expression in myeloid than in nonmyeloid cells, and in human hematopoietic progenitors upon granulocytic differentiation. In a murine model of stem cell gene therapy for X-CGD, the chimeric vector resulted in high levels of gp91(phox) expression in committed myeloid cells and granulocytes, and restored normal NADPH-oxidase activity. These findings were recapitulated in human neutrophils derived from transduced X-CGD CD34(+) cells in vivo, and suggest that the chimeric promoter will have utility for gene therapy of myeloid lineage disorders such as CGD. PMID:20978475

Santilli, Giorgia; Almarza, Elena; Brendel, Christian; Choi, Uimook; Beilin, Chiara; Blundell, Michael P; Haria, Sneha; Parsley, Kathryn L; Kinnon, Christine; Malech, Harry L; Bueren, Juan A; Grez, Manuel; Thrasher, Adrian J

2010-10-26

253

Molecular Biology of Hematopoietic Stem Cells  

Microsoft Academic Search

Human CD34+ hematopoietic stem and progenitor cells are capable of maintaining a life-long supply of the entire spectrum of blood cells dependent on systemic needs. Recent studies suggest that hematopoietic stem cells are, beyond their hematopoietic potential, able to differentiate into nonhematopoietic cell types, which could open novel avenues in the field of cellular therapy. Here, we concentrate on the

Ulrich Steidl; Ralf Kronenwett; Simona Martin; Rainer Haas

2003-01-01

254

Interferon, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia  

Microsoft Academic Search

Chronic myeloid leukemia (CML) is a clonal disease of hematopoietic stem cells caused by a reciprocal translocation of the long arms of chromosomes 9 and 22. In human leukocyte antigen A*0201 (HLA-A*0201) individuals, response af- ter interferon- (IFN-) was shown to be associated with the emergence of CML- specific cytotoxic T cells that recognize PR-1, a myeloblastin (MBN)-derived non- apeptide.

Andreas Burchert; Stefan Wolfl; Manuel Schmidt; Cornelia Brendel; Barbara Denecke; Dali Cai; Larissa Odyvanova; Tanja Lahaye; Martin C. Muller; Thomas Berg; Harald Gschaidmeier; Burghardt Wittig; Rudiger Hehlmann; Andreas Hochhaus; Andreas Neubauer

2002-01-01

255

Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML)  

Microsoft Academic Search

In core binding factors (CBF) acute myeloid leukemia (AML), the disruption of CBF?\\/? genes impairs normal hematopoietic differentiation and is supposed to cooperate with additional mutations promoting proliferation. The incidence and the prognosis of receptor tyrosine kinase (RTK) c-Kit and FLT3 mutations and Ras mutations were evaluated in 103 pediatric and adult patients with CBF-AML. c-Kit mutations were present in

N Boissel; H Leroy; B Brethon; N Philippe; S de Botton; A Auvrignon; E Raffoux; T Leblanc; X Thomas; O Hermine; B Quesnel; A Baruchel; G Leverger; H Dombret; C Preudhomme

2006-01-01

256

Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia  

Microsoft Academic Search

Acute myeloid leukemia (AML) is associated with dysregulated hematopoietic cell proliferation and increased bone marrow angiogenesis, each regulated by signaling through receptor tyrosine kinases (RTKs). SU5416 is a small molecule inhibitor of VEGF receptors, c-kit and FLT3 and therefore provides a novel opportunity to target both angiogenesis and proliferation in AML. SU5416 was assessed in a phase II hematological malignancy

Anne-Marie O’Farrell; Helene A Yuen; Beverly Smolich; Alison L Hannah; Sharianne G Louie; Weiru Hong; Alison T Stopeck; Lewis R Silverman; Jeffrey E Lancet; Judith E Karp; Maher Albitar; Julie M Cherrington; Francis J Giles

2004-01-01

257

Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse  

PubMed Central

Background Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse. Design and Methods Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy. Results Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission. Conclusions We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.

Kurosawa, Saiko; Yamaguchi, Takuhiro; Miyawaki, Shuichi; Uchida, Naoyuki; Sakura, Toru; Kanamori, Heiwa; Usuki, Kensuke; Yamashita, Takuya; Okoshi, Yasushi; Shibayama, Hirohiko; Nakamae, Hirohisa; Mawatari, Momoko; Hatanaka, Kazuo; Sunami, Kazutaka; Shimoyama, Manabu; Fujishima, Naohito; Maeda, Yoshinobu; Miura, Ikuo; Takaue, Yoichi; Fukuda, Takahiro

2010-01-01

258

Adult neurogenesis in the decapod crustacean brain: a hematopoietic connection?  

PubMed

New neurons are produced and integrated into circuits in the adult brains of many organisms, including crustaceans. In some crustacean species, the first-generation neuronal precursors reside in a niche exhibiting characteristics analogous to mammalian neurogenic niches. However, unlike mammalian niches where several generations of neuronal precursors co-exist, the lineage of precursor cells in crayfish is spatially separated allowing the influence of environmental and endogenous regulators on specific generations in the neuronal precursor lineage to be defined. Experiments also demonstrate that the first-generation neuronal precursors in the crayfish Procambarus clarkii are not self-renewing. A source external to the neurogenic niche must therefore provide cells that replenish the first-generation precursor pool, because although these cells divide and produce a continuous efflux of second-generation cells from the niche, the population of first-generation niche precursors is not diminished with growth and aging. In vitro studies show that cells extracted from the hemolymph, but not other tissues, are attracted to and incorporated into the neurogenic niche, a phenomenon that appears to involve serotonergic mechanisms. We propose that, in crayfish, the hematopoietic system may be a source of cells that replenish the niche cell pool. These and other studies reviewed here establish decapod crustaceans as model systems in which the processes underlying adult neurogenesis, such as stem cell origins and transformation, can be readily explored. Studies in diverse species where adult neurogenesis occurs will result in a broader understanding of fundamental mechanisms and how evolutionary processes may have shaped the vertebrate/mammalian condition. PMID:21929622

Beltz, Barbara S; Zhang, Yi; Benton, Jeanne L; Sandeman, David C

2011-09-01

259

Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia  

PubMed Central

The ETS transcription factor ERG plays a central role in definitive hematopoiesis, and its overexpression in acute myeloid leukemia (AML) is associated with a stem cell signature and poor prognosis. Yet how ERG causes leukemia is unclear. Here we show that pan-hematopoietic ERG expression induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and to human AML with high ERG expression. This transcriptional program was associated with activation of RAS that was required for leukemia cells growth in vitro and in vivo. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel hematopoietic enhancer validated in transgenic mice and human CD34+ normal and leukemic cells. Pim1 inhibition disrupts growth and induces apoptosis of ERG-expressing leukemic cells. The importance of the ERG/PIM1 axis is further underscored by the poorer prognosis of AML highly expressing ERG and PIM1. Thus, integrative genomic analysis demonstrates that ERG causes myeloid progenitor leukemia characterized by an induction of leukemia stem cell transcriptional programs. Pim1 and the RAS pathway are potential therapeutic targets of these high-risk leukemias.

Goldberg, Liat; Tijssen, Marloes R.; Birger, Yehudit; Hannah, Rebecca L.; Kinston, Sarah J.; Schutte, Judith; Beck, Dominik; Knezevic, Kathy; Schiby, Ginette; Jacob-Hirsch, Jasmine; Biran, Anat; Kloog, Yoel; Marcucci, Guido; Bloomfield, Clara D.; Aplan, Peter D.; Pimanda, John E.

2013-01-01

260

Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia.  

PubMed

The ETS transcription factor ERG plays a central role in definitive hematopoiesis, and its overexpression in acute myeloid leukemia (AML) is associated with a stem cell signature and poor prognosis. Yet how ERG causes leukemia is unclear. Here we show that pan-hematopoietic ERG expression induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and to human AML with high ERG expression. This transcriptional program was associated with activation of RAS that was required for leukemia cells growth in vitro and in vivo. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel hematopoietic enhancer validated in transgenic mice and human CD34(+) normal and leukemic cells. Pim1 inhibition disrupts growth and induces apoptosis of ERG-expressing leukemic cells. The importance of the ERG/PIM1 axis is further underscored by the poorer prognosis of AML highly expressing ERG and PIM1. Thus, integrative genomic analysis demonstrates that ERG causes myeloid progenitor leukemia characterized by an induction of leukemia stem cell transcriptional programs. Pim1 and the RAS pathway are potential therapeutic targets of these high-risk leukemias. PMID:23974202

Goldberg, Liat; Tijssen, Marloes R; Birger, Yehudit; Hannah, Rebecca L; Kinston, Sarah J; Schütte, Judith; Beck, Dominik; Knezevic, Kathy; Schiby, Ginette; Jacob-Hirsch, Jasmine; Biran, Anat; Kloog, Yoel; Marcucci, Guido; Bloomfield, Clara D; Aplan, Peter D; Pimanda, John E; Göttgens, Berthold; Izraeli, Shai

2013-08-23

261

GATA-1 but not SCL induces megakaryocytic differentiation in an early myeloid line.  

PubMed Central

GATA-1, a transcription factor of the 'zinc-finger' family, is required for the development of mature erythroid cells and is also highly expressed in the megakaryocytic and mast cell lineages. The helix-loop-helix gene SCL (or TAL) is expressed in the same three hematopoietic lineages as GATA-1. To explore the role of GATA-1 and SCL in hematopoietic differentiation, we introduced a new expression vector bearing each gene into the early myeloid cell line 416B, which could originally differentiate in vivo along the megakaryocytic and granulocytic lineages. Enforced expression of SCL at high levels did not provoke differentiation, but GATA-1 induced the appearance of megakaryocytes as assessed by morphology, the presence of acetylcholinesterase and a polyploid DNA content. Although GATA-1 is thought to stimulate its own transcription in erythrocytes, expression of the endogenous gene was not increased in the megakaryocytic lines; hence GATA-1 may not be autoregulatory in this lineage. Megakaryocytic differentiation was accompanied by a marked decrease in the myeloid surface marker Mac-1. The absence of mast cell or erythroid differentiation suggests that GATA-1 may not be sufficient to provoke maturation along these lineages or that these pathways are impeded in 416B cells. These results demonstrate that a member of the GATA gene family can act as an important regulator of megakaryocytic differentiation. Images

Visvader, J E; Elefanty, A G; Strasser, A; Adams, J M

1992-01-01

262

362. Evaluation the Effects of MIP1a on Ex Vivo Expansion of Cord Blood Hematopoietic Progenitor Cells in Different Culture Media  

Microsoft Academic Search

Introduction:The use of ex vivo expansion of hematopoietic progenitor cells has been suggested as a possible means to accelerate the speed of engraftment in cord blood (CB) transplantation. Macrophage inflammatory protein-1 alpha (MIP-1a) has been shown to have a role in the control of myeloid stem and progenitor cell proliferation. So the aim of this study was to evaluate the

Kamran Alimoghaddam; Mitra Khalili; Massoud Soleimani; Moezi Lili; Panthea Ghodsi; Alireza Arjmand; Ardeshir Ghavamzadeh

2006-01-01

263

Human Granulocyte Colony-Stimulating Factor: Biologic Activities and Receptor Characterization on Hematopoietic Cells and Small Cell Lung Cancer Cell Lines  

Microsoft Academic Search

Human granulocyte colony-stimulating factor (G-CSF) is a regulatory glycoprotein that stimulates the production of neutrophilic granulocytes from committed hematopoietic progenitor cells both in vitro and in vivo. In this report, we show that biosynthetic (recombinant) human G-CSF en- hances colony formation by normal human bone marrow and the human myeloid leukemic cell lines, HL-60 and KG-1, as well as nonhematopoietic

Belinda R. Avalos; Judith C. Gasson; Cyrus Hedvat; Shirley G. Quan; Gayle C. Baldwin; Richard H. Weisbart; Robert E. Williams; David W. Golde; John F. DiPersio

1990-01-01

264

Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity  

PubMed Central

Ecotropic viral integration site 1 (Evi1), a transcription factor of the SET/PR domain protein family, is essential for the maintenance of hematopoietic stem cells (HSCs) in mice and is overexpressed in several myeloid malignancies. Here, we generate reporter mice in which an internal ribosome entry site (IRES)-GFP cassette is knocked-in to the Evi1 locus. Using these mice, we find that Evi1 is predominantly expressed in long-term HSCs (LT-HSCs) in adult bone marrow, and in the hematopoietic stem/progenitor fraction in the aorta-gonad-mesonephros, placenta, and fetal liver of embryos. In both fetal and adult hematopoietic systems, Evi1 expression marks cells with long-term multilineage repopulating activity. When combined with conventional HSC surface markers, sorting according to Evi1 expression markedly enhances purification of cells with HSC activity. Evi1 heterozygosity leads to marked impairment of the self-renewal capacity of LT-HSCs, whereas overexpression of Evi1 suppresses differentiation and boosts self-renewal activity. Reintroduction of Evi1, but not Mds1-Evi1, rescues the HSC defects caused by Evi1 heterozygosity. Thus, in addition to documenting a specific relationship between Evi1 expression and HSC self-renewal activity, these findings highlight the utility of Evi1-IRES-GFP reporter mice for the identification and sorting of functional HSCs.

Kataoka, Keisuke; Sato, Tomohiko; Yoshimi, Akihide; Goyama, Susumu; Tsuruta, Takako; Kobayashi, Hiroshi; Shimabe, Munetake; Arai, Shunya; Nakagawa, Masahiro; Imai, Yoichi; Kumano, Keiki; Kumagai, Katsuyoshi; Kubota, Naoto; Kadowaki, Takashi

2011-01-01

265

Estrone potentiates myeloid cell differentiation  

Microsoft Academic Search

Hormones such as 1?,25-dihydroxy vitamin D3 (D3), all-trans retinoic acid, and 9-cis retinoic acid stimulate differentiation of myeloid progenitor cells via their interaction with specific hormone receptors. However, the sensitivity of cells to these agents is not merely governed by the expression of their receptors and the availability of ligand to bind them. Recent studies from our group suggested that

Joanne C Mountford; Christopher M Bunce; Susan V Hughes; Mark T Drayson; David Webb; Geoffery Brown; Martin Hewison

1999-01-01

266

Effects of graded doses of 1 MeV fission neutrons or X-rays on the murine hematopoietic stroma.  

National Technical Information Service (NTIS)

The acute radiosensitivity in-vivo of the murine hematopoietic stroma for 1 MeV fission neutrons or 300 kVp X-rays was determined. Two different assays were used: (1) and in vitro clonogenic assay for fibro-blast precursor cells (CFU-F) and (2) subcutaneo...

E. I. M. Meijne R. Huiskamp R. E. Ploemacher O. Vos

1991-01-01

267

Effects of Graded Doses of 1 MeV Fission Neutrons or X-rays on the Murine Hematopoietic Stroma.  

National Technical Information Service (NTIS)

The acute radiosensitivity in vivo of the murine hematopoietic stroma for 1 MeV fission neutrons or 300 kVp X-rays was determined. Two different assays were used: (1) an in vitro clonogenic assay for fibroblast precursor cells (CFU-F) and (2) subcutaneous...

E. I. M. Meijne R. E. Ploemacher O. Vos R. Huiskamp

1992-01-01

268

The Flk1-Cre-mediated deletion of ETV2 defines its narrow temporal requirement during embryonic hematopoietic development.  

PubMed

During embryonic development, the emergence of hematopoiesis and vasculogenesis is tightly associated, with many transcription factors implicated in both developmental processes. Among those factors, ETV2 acts at the top of the hierarchy and controls the formation of both lineages. However, it is not known at which stage of mesoderm development ETV2 is acting and whether ETV2 activity is further required once mesodermal precursors have been specified to the hematopoietic and endothelial fates. In this study, we characterize the developmental window during which ETV2 expression is required for hematopoietic and endothelial development. Using cre-mediated deletion of ETV2, we demonstrate that ETV2 is acting prior to or at the time of FLK1 expression in mesodermal precursors to initiate the hematopoietic and endothelial program. Using the in vitro differentiation of embryonic stem cells as a model system, we further show that ETV2 re-expression in Etv2(-/-) Flk1-negative precursors drives hematopoiesis specification and switches on the expression of most genes known to be implicated in hematopoietic and endothelial development. Among the downstream targets of ETV2, we identify the transcription factors SCL, GATA2, and FLI1 known to operate a recursive loop controlling hematopoietic development. Surprisingly, SCL re-expression in Etv2(-/-) cells fully rescues hematopoiesis, while the re-expression of FLI1 or GATA2 promotes only a very limited rescue. Altogether, our data establish that ETV2 is required very transiently to specify mesodermal precursors to hematopoiesis and vasculogenesis and that SCL is one of the key downstream targets of ETV2 in controlling hematopoietic specification. PMID:22570122

Wareing, Sarah; Mazan, Andrzej; Pearson, Stella; Göttgens, Berthold; Lacaud, Georges; Kouskoff, Valerie

2012-07-01

269

Isolation, growth and identification of colony-forming cells with erythroid, myeloid, dendritic cell and NK-cell potential from human fetal liver  

PubMed Central

The study of hematopoietic stem cells (HSCs) and the process by which they differentiate into committed progenitors has been hampered by the lack of in vitro clonal assays that can support erythroid, myeloid and lymphoid differentiation. We describe a method for the isolation from human fetal liver of highly purified candidate HSCs and progenitors based on the phenotypes CD38-CD34++ and CD38+CD34++, respectively. We also describe a method for the growth of colony-forming cells (CFCs) from these cell populations, under defined culture conditions, that supports the differentiation of erythroid, CD14/CD15+ myeloid, CD1a+ dendritic cell and CD56+ NK cell lineages. Flow cytometric analyses of individual colonies demonstrate that CFCs with erythroid, myeloid and lymphoid potential are distributed among both the CD38- and CD38+ populations of CD34++ progenitors.

Suskind, David L.; Barcena, Alicia

2002-01-01

270

Interplay among Etsrp/ER71, Scl, and Alk8 signaling controls endothelial and myeloid cell formation  

PubMed Central

Vascular endothelial and myeloid cells have been proposed to originate from a common precursor cell, the hemangioblast. The mechanism of endothelial and myeloid cell specification and differentiation is poorly understood. We have previously described the endothelial-specific zebrafish Ets1-related protein (Etsrp), which was both necessary and sufficient to initiate vasculogenesis in the zebrafish embryos. Here we identify human Etv2/ER71 and mouse ER71 proteins as functional orthologs of Etsrp. Overexpression of mouse ER71 and Etsrp caused strong expansion of hemangioblast and vascular endothelial lineages in a zebrafish embryo. In addition, we show that etsrp is also required for the formation of myeloid but not erythroid cells. In the absence of etsrp function, the number of granulocytes and macrophages is greatly reduced. Etsrp overexpression causes expansion of both myeloid and vascular endothelial lineages. Analysis of mosaic embryos indicates that etsrp functions cell autonomously in inducing myeloid lineage. We further demonstrate that the choice of endothelial versus myeloid fate depends on a combinatorial effect of etsrp, scl, and alk8 genes.

Gomez, Gustavo; Zhao, Yan; Park, Changwon; Choi, Kyunghee

2008-01-01

271

Characterization of hematopoietic progenitor cells that express the transcription factor SCL, using a lacZ "knock-in" strategy  

PubMed Central

Gene targeting experiments have demonstrated that the transcription factor SCL is essential for primitive and definitive hematopoiesis in the mouse. To study the functional properties of hematopoietic cells expressing SCL, we have generated mutant mice (SCLlacZ/w) in which the Escherichia coli lacZ reporter gene has been “knocked in” to the SCL locus, thereby linking ?-galactosidase expression to transcription from the SCL promoter. Bone marrow cells from heterozygous SCLlacZ/w mice were sorted into fractions expressing high, intermediate and low levels of ?-galactosidase (designated lacZhigh, lacZint, and lacZneg). Cells that were lacZhigh or lacZint were enriched for day 12 spleen colony-forming units and myeloid and erythroid colony-forming cells (CFCs). These fractions included >99% of the erythroid and >90% of the myeloid CFCs. Culture of sorted bone marrow populations on stromal cells secreting interleukin-7 or in fetal thymic organ cultures showed that B and T lymphoid progenitors were also present in the lacZhigh and lacZint fractions. These data provide a functional correlation between SCL expression and colony-forming ability in immature hematopoietic cells. Our data also suggested that expression of SCL was transient and confined to hematopoietic stem and/or progenitor cells, because the differentiated progeny of most lineages (except the erythroid) were ?-galactosidase-negative.

Elefanty, Andrew G.; Begley, C. Glenn; Metcalf, Donald; Barnett, Louise; Kontgen, Frank; Robb, Lorraine

1998-01-01

272

In vitro myelosuppressive effects of the parvovirus minute virus of mice (MVMi) on hematopoietic stem and committed progenitor cells.  

PubMed

The interaction of two strains of the parvovirus minute virus of mice (MVM) with the mouse hematopoietic system has been studied. The immunosuppressive strain MVMi, but not the prototype virus MVMp, inhibited hematopoiesis in vitro, as judged by colony-forming assays of the erythroid burst-forming unit and granulocyte-monocyte colony-forming unit (CFU-GM) progenitors. Interestingly, primitive hematopoietic cells of the stem compartment (CFU-S12d), were equally susceptible to the MVMi cytotoxic infection, unravelling an unprecedented feature of virus-hematopoiesis interactions. The replication of both strains of MVM virus was evaluated in primary myeloid cells of long-term bone marrow cultures. A high viral DNA synthesis and maturation was observed in MVMi-infected myeloid cells, but it was undetectable in MVMp infections; moreover, the expression of the cytotoxic nonstructural NS-1 protein, a more reliable parameter of cell permissiveness to MVM infection, was only detected in MVMi-infected cells. Correspondingly, MVMi was propagated to high titers of infectious virus and it mediated an acute myelosuppression in these cultures. We conclude that MVMi has a wider tropism than was previously suspected and it is proposed that cytotoxic infection of hematopoietic stem cells, besides that of committed progenitors, may provide an additional basis to understand the pathogenesis of certain animal and human bone marrow failures of viral etiology. PMID:1847313

Segovia, J C; Real, A; Bueren, J A; Almendral, J M

1991-03-01

273

The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression  

PubMed Central

Menin is the product of the tumor suppressor gene Men1 that is mutated in the inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1). Menin has been shown to interact with SET-1 domain-containing histone 3 lysine 4 (H3K4) methyltransferases including mixed lineage leukemia proteins to regulate homeobox (Hox) gene expression in vitro. Using conditional Men1 knockout mice, we have investigated the requirement for menin in hematopoiesis and myeloid transformation. Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus. Consistent with signaling downstream of menin, ectopic expression of both Hoxa9 and Meis1 rescues colony formation defects in Men1-excised bone marrow. Moreover, Men1 excision also suppresses proliferation of leukemogenic mixed lineage leukemia-AF9 fusion-protein-transformed myeloid cells and Hoxa9 expression. These studies uncover an important role for menin in both normal hematopoiesis and myeloid transformation and provide a mechanistic understanding of menin's function in these processes that may be used for therapy.

Chen, Ya-Xiong; Yan, Jizhou; Keeshan, Karen; Tubbs, Anthony T.; Wang, Haoren; Silva, Albert; Brown, Eric J.; Hess, Jay L.; Pear, Warren S.; Hua, Xianxin

2006-01-01

274

Assessment of Benzene-Induced Hematotoxicity Using a Human-Like Hematopoietic Lineage in NOD/Shi-scid/IL-2R?null Mice  

PubMed Central

Despite recent advancements, it is still difficult to evaluate in vivo responses to toxicants in humans. Development of a system that can mimic the in vivo responses of human cells will enable more accurate health risk assessments. A surrogate human hematopoietic lineage can be established in NOD/Shi-scid/IL-2R?null (NOG) mice by transplanting human hematopoietic stem/progenitor cells (Hu-NOG mice). Here, we first evaluated the toxic response of human-like hematopoietic lineage in NOG mice to a representative toxic agent, benzene. Flow cytometric analysis showed that benzene caused a significant decrease in the number of human hematopoietic stem/progenitor cells in the bone marrow and the number of human leukocytes in the peripheral blood and hematopoietic organs. Next, we established chimeric mice by transplanting C57BL/6 mouse-derived bone marrow cells into NOG mice (Mo-NOG mice). A comparison of the degree of benzene-induced hematotoxicity in donor-derived hematopoietic lineage cells within Mo-NOG mice indicated that the toxic response of Hu-NOG mice reflected interspecies differences in susceptibilities to benzene. Responses to the toxic effects of benzene were greater in lymphoid cells than in myeloid cells in Mo-NOG and Hu-NOG mice. These findings suggested that Hu-NOG mice may be a powerful in vivo tool for assessing hematotoxicity in humans, while accounting for interspecies differences.

Takahashi, Masayuki; Tsujimura, Noriyuki; Yoshino, Tomoko; Hosokawa, Masahito; Otsuka, Kensuke; Matsunaga, Tadashi; Nakasono, Satoshi

2012-01-01

275

Restricted Access to Myeloid Cells Explained  

PubMed Central

The lentiviral accessory protein, Vpx, is known to counteract a restriction factor that is specific to myeloid cells, such as macrophages and dendritic cells. This review summarizes the findings in two seminal studies that identify SAMHD1 as the cellular protein that is responsible for myeloid cell restriction, and establish the existence of other types of restriction in these cells.

Planelles, Vicente

2011-01-01

276

Ethanol exhibits specificity in its effects on differentiation of hematopoietic progenitors1  

PubMed Central

Ethanol is a known teratogen but the mechanisms by which this simple compound affects fetal development remain unresolved. The goal of the current study was to determine the mechanism by which ethanol affects lymphoid differentiation using an in vitro model of ethanol exposure. Primitive hematopoietic oligoclonal neonatal progenitor cells (ONP), with the phenotype Lin?HSAloCD43loSca-1?c-Kit+ that are present in neonatal but not adult bone marrow were sorted from the bone marrow of 2-week-old C57BL/6J mice and cultured under conditions that favor either B cell or myeloid cell differentiation with or without addition of ethanol. The overall growth of the ONP cells was not significantly affected by inclusion of up to 100mM ethanol in the culture medium. However, the differentiation of the progenitor cells along the B-cell pathway was significantly impaired by ethanol in a dose dependent manner. Exposure of ONP cells to 100mM ethanol resulted in greater than 95% inhibition of B cell differentiation. Conversely, ethanol concentrations up to and including 100mM had no significant effect on differentiation along the myeloid pathway. The effect of ethanol on transcription factor expression was consistent with the effects on differentiation. ONP cells grown in 100mM ethanol failed to up-regulate Pax5 and EBF, transcriptional regulators that are necessary for B cell development. However, ethanol had no significant effect on the up-regulation of PU.1, a transcription factor that, when expressed in high concentration, favors myeloid cell development. Taken together, these results suggest that ethanol has specificity in its effects on differentiation of hematopoietic progenitors.

Wang, Hao; Zhou, Huijuan; Chervenak, Robert; Moscatello, Kim M.; Brunson, Lee Ellen; Chervenak, Deborah C.; Wolcott, R. Michael

2009-01-01

277

DNA sequencing of a cytogenetically normal acute myeloid leukemia genome  

PubMed Central

Lay Summary Acute myeloid leukemia is a highly malignant hematopoietic tumor that affects about 13,000 adults yearly in the United States. The treatment of this disease has changed little in the past two decades, since most of the genetic events that initiate the disease remain undiscovered. Whole genome sequencing is now possible at a reasonable cost and timeframe to utilize this approach for unbiased discovery of tumor-specific somatic mutations that alter the protein-coding genes. Here we show the results obtained by sequencing a typical acute myeloid leukemia genome and its matched normal counterpart, obtained from the patient’s skin. We discovered 10 genes with acquired mutations; two were previously described mutations thought to contribute to tumor progression, and 8 were novel mutations present in virtually all tumor cells at presentation and relapse, whose function is not yet known. Our study establishes whole genome sequencing as an unbiased method for discovering initiating mutations in cancer genomes, and for identifying novel genes that may respond to targeted therapies. We used massively parallel sequencing technology to sequence the genomic DNA of tumor and normal skin cells obtained from a patient with a typical presentation of FAB M1 Acute Myeloid Leukemia (AML) with normal cytogenetics. 32.7-fold ‘haploid’ coverage (98 billion bases) was obtained for the tumor genome, and 13.9-fold coverage (41.8 billion bases) was obtained for the normal sample. Of 2,647,695 well-supported Single Nucleotide Variants (SNVs) found in the tumor genome, 2,588,486 (97.7%) also were detected in the patient’s skin genome, limiting the number of variants that required further study. For the purposes of this initial study, we restricted our downstream analysis to the coding sequences of annotated genes: we found only eight heterozygous, non-synonymous somatic SNVs in the entire genome. All were novel, including mutations in protocadherin/cadherin family members (CDH24 and PCLKC), G-protein coupled receptors (GPR123 and EBI2), a protein phosphatase (PTPRT), a potential guanine nucleotide exchange factor (KNDC1), a peptide/drug transporter (SLC15A1), and a glutamate receptor gene (GRINL1B). We also detected previously described, recurrent somatic insertions in the FLT3 and NPM1 genes. Based on deep readcount data, we determined that all of these mutations (except FLT3) were present in nearly all tumor cells at presentation, and again at relapse 11 months later, suggesting that the patient had a single dominant clone containing all of the mutations. These results demonstrate the power of whole genome sequencing to discover novel cancer-associated mutations.

Ley, Timothy J; Mardis, Elaine R; Ding, Li; Fulton, Bob; McLellan, Michael D; Chen, Ken; Dooling, David; Dunford-Shore, Brian H; McGrath, Sean; Hickenbotham, Matthew; Cook, Lisa; Abbott, Rachel; Larson, David E; Koboldt, Dan C; Pohl, Craig; Smith, Scott; Hawkins, Amy; Abbott, Scott; Locke, Devin; Hillier, LaDeana W; Miner, Tracie; Fulton, Lucinda; Magrini, Vincent; Wylie, Todd; Glasscock, Jarret; Conyers, Joshua; Sander, Nathan; Shi, Xiaoqi; Osborne, John R; Minx, Patrick; Gordon, David; Chinwalla, Asif; Zhao, Yu; Ries, Rhonda E; Payton, Jacqueline E; Westervelt, Peter; Tomasson, Michael H; Watson, Mark; Baty, Jack; Ivanovich, Jennifer; Heath, Sharon; Shannon, William D; Nagarajan, Rakesh; Walter, Matthew J; Link, Daniel C; Graubert, Timothy A; DiPersio, John F; Wilson, Richard K

2008-01-01

278

Interleukin 7-dependent B lymphocyte precursor cells are ultrasensitive to apoptosis  

PubMed Central

We have compared the sensitivity of clonogenic interleukin 7 (IL-7)- dependent murine B cell precursors with that of clonogenic mature B cells and myeloid precursors to alpha-particles from plutonium-238 and X radiation. All three populations are relatively sensitive, but B cell precursors are ultrasensitive. This differential sensitivity is also observed with corticosteroid, etoposide, and cisplatin, all apoptosis- inducing drugs used in the treatment of leukemia and other cancers. Further, we show that x-rays and drugs induce the bulk of the B cell precursor population to undergo rapid apoptosis, despite the continued presence of IL-7. B cell precursors were found to express very low levels of BCL-2 protein compared with mature splenic B cells and their resistance to x-rays and corticosteroid could be enhanced by expression of a BCL-2 transgene. These data have important implications for normal lymphopoiesis and for the behavior of leukemic lymphoid precursor cells.

1994-01-01

279

Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning  

PubMed Central

Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55 years; range, 5-74 years) received related (n = 498) or unrelated (n = 336) HCT after 2 Gy total body irradiation alone (n = 171) or combined with fludarabine (90 mg/m2; n = 663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing nonrelapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) in remission (CR), low-grade or mantle cell non-Hodgkin lymphoma (NHL) (CR + partial remission [PR]), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of more than 0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high-grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT.

Kahl, Christoph; Storer, Barry E.; Sandmaier, Brenda M.; Mielcarek, Marco; Maris, Michael B.; Blume, Karl G.; Niederwieser, Dietger; Chauncey, Thomas R.; Forman, Stephen J.; Agura, Edward; Leis, Jose F.; Bruno, Benedetto; Langston, Amelia; Pulsipher, Michael A.; McSweeney, Peter A.; Wade, James C.; Epner, Elliot; Bo Petersen, Finn; Bethge, Wolfgang A.; Maloney, David G.

2007-01-01

280

Hematopoietic Stem Cell Gene Therapy  

Microsoft Academic Search

Gene therapy applications that target hematopoietic stem cells (HSCs) offer great potential for the treatment of hematologic\\u000a disease. Despite this promise, clinical success has been limited by poor rates of gene transfer, poor engraftment of modified\\u000a cells, and poor levels of gene expression. We describe here the basic approach used for HSC gene therapy, briefly review some\\u000a of the seminal

David W. Emery; Tamon Nishino; Ken Murata; Michalis Fragkos; George Stamatoyannopoulos

2002-01-01

281

Diagnostic Value II: Hematopoietic Malignancies  

Microsoft Academic Search

\\u000a Telomerase activity has been suggested to play a critical role in hematopoietic stem cell (HSC) maintenance. The most primitive\\u000a HSCs, long-term HSCs, present in specific niches where they can remain mitotically quiescent for long periods of time, exhibiting\\u000a a low level of telomerase activity. Short-term HSCs undergo asymmetric cell divisions with upregulated telomerase activity.\\u000a Leukemic stem cells (LSCs) have shortened

H. Ohyashiki Junko; Ohyashiki Kazuma

282

Download Hematopoietic & Lymphoid Database Software  

Cancer.gov

Before downloading Hematopoietic Database Software version 2.2, you must read and sign the Terms of Use Agreement below and complete the registration form. After completing the form you will receive an e-mail with a link to the software download. The download link may be used once and then it will expire. If your link has expired, request a new one using the Already Registered?

283

Acute myeloid leukemia stem cells and CD33-targeted immunotherapy  

PubMed Central

Although the identification of cancer stem cells as therapeutic targets is now actively being pursued in many human malignancies, the leukemic stem cells in acute myeloid leukemia (AML) are a paradigm of such a strategy. Heterogeneity of these cells was suggested by clonal analyses indicating the existence of both leukemias resulting from transformed multipotent CD33? stem cells as well others arising from, or predominantly involving, committed CD33+ myeloid precursors. The latter leukemias, which may be associated with an intrinsically better prognosis, offer a particularly attractive target for stem cell-directed therapies. Targeting the CD33 differentiation antigen with gemtuzumab ozogamicin was the first attempt of such an approach. Emerging clinical data indicate that gemtuzumab ozogamicin is efficacious not only for acute promyelocytic leukemia but, in combination with conventional chemotherapy, also for other favorable- and intermediate-risk AMLs, providing the first proof-of-principle evidence for the validity of this strategy. Herein, we review studies on the nature of stem cells in AML, discuss clinical data on the effectiveness of CD33-directed therapy, and consider the mechanistic basis for success and failure in various AML subsets.

Appelbaum, Frederick R.; Estey, Elihu H.; Bernstein, Irwin D.

2012-01-01

284

Dasatinib, Cytarabine, and Idarubicin in Treating Patients With High-Risk Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2013-09-16

285

Lineage tracing of Pf4-Cre marks hematopoietic stem cells and their progeny.  

PubMed

The development of a megakaryocyte lineage specific Cre deleter, using the Pf4 (CXCL4) promoter (Pf4-Cre), was a significant step forward in the specific analysis of platelet and megakaryocyte cell biology. However, in the present study we have employed a sensitive reporter-based approach to demonstrate that Pf4-Cre also recombines in a significant proportion of both fetal liver and bone marrow hematopoietic stem cells (HSCs), including the most primitive fraction containing the long-term repopulating HSCs. Consequently, we demonstrate that Pf4-Cre activity is not megakaryocyte lineage-specific but extends to other myeloid and lymphoid lineages at significant levels between 15-60%. Finally, we show for the first time that Pf4 transcripts are present in adult HSCs and primitive hematopoietic progenitor cells. These results have fundamental implications for the use of the Pf4-Cre mouse model and for our understanding of a possible role for Pf4 in the development of the hematopoietic lineage. PMID:23300543

Calaminus, Simon D J; Guitart, Amelie V; Guitart, Amelie; Sinclair, Amy; Schachtner, Hannah; Watson, Steve P; Holyoake, Tessa L; Kranc, Kamil R; Machesky, Laura M

2012-12-27

286

Lineage Tracing of Pf4-Cre Marks Hematopoietic Stem Cells and Their Progeny  

PubMed Central

The development of a megakaryocyte lineage specific Cre deleter, using the Pf4 (CXCL4) promoter (Pf4-Cre), was a significant step forward in the specific analysis of platelet and megakaryocyte cell biology. However, in the present study we have employed a sensitive reporter-based approach to demonstrate that Pf4-Cre also recombines in a significant proportion of both fetal liver and bone marrow hematopoietic stem cells (HSCs), including the most primitive fraction containing the long-term repopulating HSCs. Consequently, we demonstrate that Pf4-Cre activity is not megakaryocyte lineage-specific but extends to other myeloid and lymphoid lineages at significant levels between 15–60%. Finally, we show for the first time that Pf4 transcripts are present in adult HSCs and primitive hematopoietic progenitor cells. These results have fundamental implications for the use of the Pf4-Cre mouse model and for our understanding of a possible role for Pf4 in the development of the hematopoietic lineage.

Schachtner, Hannah; Watson, Steve P.; Holyoake, Tessa L.; Kranc, Kamil R.; Machesky, Laura M.

2012-01-01

287

Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: Experimental models and clinical perspectives  

PubMed Central

In this review, we highlight some of recent studies underscoring the importance of the tumor microenvironment, especially the role of bone marrow-derived myeloid cells, in restoring tumor growth after irradiation. Myeloid cells are hematopoietic cells that give rise to monocytes and macrophages in the peripheral blood and tissues. These cells have been shown to be proangiogenic in tumors promoting tumor growth. We also discuss our previously unpublished results on the effect of irradiation on the tumor vasculature including pericyte and basement membrane coverage to the endothelium of tumor blood vessels. We summarize the clinical significance of these studies including the use of MMP-9 inhibitors, administering white blood cell boosters, or planning safety margin of tumor volumes, in order to improve overall clinical benefits in cancer patients treated with radiotherapy.

Ahn, G-One; Brown, J. Martin

2010-01-01

288

Prognosis of patients with core binding factor acute myeloid leukemia after first relapse.  

PubMed

Core binding factor acute myeloid leukemia is known to have a favorable prognosis, however, there have been no detailed analyses on prognostic factors after first relapse. Using a nationwide database, we retrospectively analyzed core binding factor acute myeloid leukemia patients who relapsed after being treated with chemotherapy alone during their first complete remission. Of a total of 397 patients who were diagnosed with core binding factor acute myeloid leukemia, 208 experienced a first relapse, and analyses were performed in 139 patients for whom additional data were available. In the entire cohort, the overall survival rate after relapse was 48% at 3 years. By multivariate analysis, younger age at diagnosis, a longer interval before relapse, and inv(16) were shown to be independently associated with better survival after relapse. Although there was no significant difference in survival after relapse between patients who underwent allogeneic hematopoietic cell transplantation and those who did not in the overall series of relapsed patients, we found that transplantation significantly improved survival among patients who had t(8;21) (54% versus 26% at 3 years, P=0.002). In addition, among patients with t(8;21), those who had different cytogenetics at relapse had a significantly improved survival after transplantation, while those who had same cytogenetics did not. We showed that the prognosis differs significantly and optimal treatment strategies may vary between groups of patients with core binding factor acute myeloid leukemia with different cytogenetic profiles at relapse. These findings may help to guide therapeutic decisions after first relapse. PMID:23716553

Kurosawa, Saiko; Miyawaki, Shuichi; Yamaguchi, Takuhiro; Kanamori, Heiwa; Sakura, Toru; Moriuchi, Yukiyoshi; Sano, Fumiaki; Kobayashi, Takeshi; Yasumoto, Atsushi; Hatanaka, Kazuo; Yanada, Masamitsu; Nawa, Yuichiro; Takeuchi, Jin; Nakamura, Yukinori; Fujisawa, Shin; Shibayama, Hirohiko; Miura, Ikuo; Fukuda, Takahiro

2013-05-28

289

The origin and evolution of mutations in acute myeloid leukemia.  

PubMed

Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse. PMID:22817890

Welch, John S; Ley, Timothy J; Link, Daniel C; Miller, Christopher A; Larson, David E; Koboldt, Daniel C; Wartman, Lukas D; Lamprecht, Tamara L; Liu, Fulu; Xia, Jun; Kandoth, Cyriac; Fulton, Robert S; McLellan, Michael D; Dooling, David J; Wallis, John W; Chen, Ken; Harris, Christopher C; Schmidt, Heather K; Kalicki-Veizer, Joelle M; Lu, Charles; Zhang, Qunyuan; Lin, Ling; O'Laughlin, Michelle D; McMichael, Joshua F; Delehaunty, Kim D; Fulton, Lucinda A; Magrini, Vincent J; McGrath, Sean D; Demeter, Ryan T; Vickery, Tammi L; Hundal, Jasreet; Cook, Lisa L; Swift, Gary W; Reed, Jerry P; Alldredge, Patricia A; Wylie, Todd N; Walker, Jason R; Watson, Mark A; Heath, Sharon E; Shannon, William D; Varghese, Nobish; Nagarajan, Rakesh; Payton, Jacqueline E; Baty, Jack D; Kulkarni, Shashikant; Klco, Jeffery M; Tomasson, Michael H; Westervelt, Peter; Walter, Matthew J; Graubert, Timothy A; DiPersio, John F; Ding, Li; Mardis, Elaine R; Wilson, Richard K

2012-07-20

290

The glutathione disulfide mimetic, NOV-002, inhibits cyclophosphamide-induced hematopoietic and immune suppression by reducing oxidative stress  

PubMed Central

The oxidized glutathione mimetic NOV-002, is a unique anti-tumor agent that not only has the ability to inhibit tumor cell proliferation, survival, and invasion, but in some settings can also ameliorate cytotoxic chemotherapy-induced hematopoietic and immune suppression. However, the mechanisms by which NOV-002 protects the hematopoietic and immune systems against the cytoxic effects of chemotherapy are not known. Therefore, in the present study we investigated the mechanisms of action of NOV-002 using a mouse model in which hematopoietic and immune suppression was induced by cyclophosphamide (CTX) treatment. We found that NOV-002 treatment in a clinically comparable dose regimen attenuated CTX-induced reduction in bone marrow hematopoietic stem and progenitor cells (HSPCs), and reversed the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), which led to a significant improvement in hematopoietic and immune functions. These effects of NOV-002 may be attributable to its ability to modulate cellular redox. This suggestion is supported by the finding that NOV-002 treatment upregulated the expression of superoxide dismutase 3 and glutathione peroxidase 2 in HSPCs; inhibited CTX-induced increases in reactive oxygen species production in HSPCs and MDSCs; and attenuated CTX-induced reduction of the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in splenocytes. These findings provide a better understanding of the mechanisms whereby NOV-002 modulates chemotherapy-induced myelosuppression and immune dysfunction, and a stronger rationale for clinical utilization of NOV-002 has the potential to be utilized to reduce chemotherapy-induced hematopoietic and immune suppression.

Diaz-Montero, C. Marcela; Wang, Yong; Shao, Lijian; Feng, Wei; Zidan, Abdel-Aziz; Pazoles, Christopher J.; Montero, Alberto J.; Zhou, Daohong

2012-01-01

291

Serum concentrations of nitrite and malondialdehyde as markers of oxidative stress in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors  

PubMed Central

Background: Chronic myeloid leukemia is a neoplasm characterized by clonal expansion of hematopoietic progenitor cells resulting from the (9:22)(q34,11) translocation. The tyrosine kinase abl fusion protein,the initial leukemogenic event in chronic myeloid leukemia, is constitutively activated thus inducing the production of reactive oxygen species. Of particular relevance is the fact that an increase in reactive oxygen species can facilitate genomic instability and may contribute to disease progression. Objetive: To evaluate oxidative stress by determining the levels of malondialdehyde and nitrite in chronic myeloid leukemia patients under treatment with 1st and 2nd generation tyrosine kinase inhibitors monitored at a referral hospital in Fortaleza, Ceará. Methods: A cross-sectional study was performed of 64 male and female adults. Patients were stratified according to treatment. The levels of malondialdehyde and nitrite were determined by spectrophotometry. Statistical differences between groups were observed using the Student t-test and Fisher's exact test. The results are expressed as mean ± standard error of mean. The significance level was set for a p-value < 0.05 in all analyses. Results: The results show significantly higher mean concentrations of nitrite and malondialdehyde in chronic myeloid leukemia patients using second-generation tyrosine kinase inhibitors compared to patients on imatinib. Conclusion: It follows that chronic myeloid leukemia patients present higher oxidative activity and that the increases in oxidative damage markers can indicate resistance to 1st generation tyrosine kinase inhibitors.

Petrola, Maria Juracy; de Castro, Alana Joselina Montenegro; Pitombeira, Maria Helena da Silva; Barbosa, Maritza Cavalcante; Quixada, Acy Telles de Souza; Duarte, Fernando Barroso; Goncalves, Romelia Pinheiro

2012-01-01

292

Dysregulated hematopoiesis caused by mammary cancer is associated with epigenetic changes and hox gene expression in hematopoietic cells.  

PubMed

Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colony-stimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes. Cancer Res; 73(19); 5892-904. ©2013 AACR. PMID:23913828

Sio, Alexander; Chehal, Manreet K; Tsai, Kevin; Fan, Xueling; Roberts, Morgan E; Nelson, Brad H; Grembecka, Jolanta; Cierpicki, Tomasz; Krebs, Danielle L; Harder, Kenneth W

2013-08-01

293

Novel retroviral vectors for efficient expression of the multidrug resistance (mdr-1) gene in early hematopoietic cells.  

PubMed Central

We present data that retroviral gene expression in early hematopoietic cells is subjected to transcriptional controls similar to those previously described for embryonic stem cells. Transient transfection experiments revealed that both the viral enhancer region in the U3 region of the long terminal repeat as well as a repressor element coincident with the primer binding site of Moloney leukemia viruses are limiting for expression in hematopoietic cells in a differentiation-dependent manner. Within the group of Moloney leukemia virus-related viruses, only the myeloproliferative sarcoma virus showed high enhancer activity in myeloid (including erythroid) cells. In contrast, enhancer regions related to the Friend mink cell focus-forming viruses mediate much higher gene expression levels in both multipotent and lineage-committed myeloid cells. In addition, transcriptional repression related to sequences in the primer binding site of Moloney leukemia virus-derived vectors is also found in early hematopoietic cells and can be overcome by using the corresponding sequences of the murine embryonic stem cell virus. On the basis of these results, two types of novel retroviral hybrid vectors were developed; they combine the U3 regions of either the Friend mink cell focus-forming virus family or the myeloproliferative sarcoma virus with the primer binding site of the murine embryonic stem cell virus. When used to express the human multiple drug resistance gene, these vectors substantially improve protection to cytostatic drugs in transduced hematopoietic cell lines FDC-Pmix, TF-1, and K-562 in comparison with Moloney leukemia virus-derived vectors presently used for the stem cell protection approach in somatic gene therapy.

Baum, C; Hegewisch-Becker, S; Eckert, H G; Stocking, C; Ostertag, W

1995-01-01

294

Myeloid sarcoma of the maxillary bone.  

PubMed

Myeloid sarcoma (MS) is a malignant tumour of myeloblasts rarely occurring in the maxillary bone. The tumour may precede or be concurrent with leukaemic infiltration of the bone marrow or herald blastic transformation of a myelodysplastic syndrome or a chronic myeloproliferative disorder. Myeloid sarcoma is uncommon in the oral cavity, but it can involve the palate, gingiva, extraction socket, and cheek. Recognition and diagnosis of myeloid sarcoma involving the soft tissues of the oral cavity in an otherwise asymptomatic patient is important and mandates an appropriate haematological diagnostic workup. We herein report on a new case without any evidence of haematological disorders. We discuss the pathological diagnosis and the therapeutical approaches. PMID:16519776

Goteri, G; Ascani, G; Messi, M; Filosa, A; Segura-Egea, J J; Rubini, C; Bullon, P

2006-04-01

295

Regulation of hematopoietic stem cell growth  

Microsoft Academic Search

Hematopoietic stem cells (HSC) must balance self-renewal and differentiation to provide sufficient primitive cells to sustain hematopoiesis, while generating more mature cells with specialized capabilities. The enhanced self-renewal capacity of primitive HSCs enables their ability to sustain hematopoiesis throughout decades of life and their ability to repopulate a host when used therapeutically in bone marrow transplantation. However, hematopoietic cell perturbations

E C Attar; D T Scadden

2004-01-01

296

Fatal human metapneumovirus infection following allogeneic hematopoietic stem cell transplantation.  

PubMed

Respiratory viruses are an important yet underestimated cause of infectious morbidity and mortality in immunocompromised children and adolescents. Here, we report the occurrence of fatal lower respiratory tract disease associated with human metapneumovirus (HMPV) infection in a 10-year-old girl with chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation (HSCT) for secondary chronic myeloid leukemia. Symptoms occurred 8 months after HSCT while on immunosuppression with 0.2 mg/kg/day of prednisone, and presented as dry cough, bilateral pneumonitis, and progressive respiratory distress. Non-invasive and invasive microbiological investigations revealed HMPV type B as the sole pathogen. Histopathological findings showed interstitial and intra-alveolar pneumonitis with profound alveolar cell damage. The patient was treated with intravenous and oral ribavirin and polyvalent immunoglobulins, but ultimately died from respiratory failure. The case reflects the potentially fatal impact of infections by respiratory viruses in immunocompromised patients and the need for effective approaches to their prevention and treatment. PMID:23551689

Dokos, C; Masjosthusmann, K; Rellensmann, G; Werner, C; Schuler-Lüttmann, S; Müller, K-M; Schiborr, M; Ehlert, K; Groll, A H

2013-04-01

297

Invertebrate hematopoiesis: an astakine-dependent novel hematopoietic factor.  

PubMed

A novel factor, named crustacean hematopoietic factor (CHF), was identified from a library of suppression subtractive hybridization with the aim to find downstream genes of an invertebrate cytokine, astakine 1, in the freshwater crayfish Pacifastacus leniusculus. CHF is a small cysteine-rich protein (?9 kDa) with high similarity to the N-terminal region of vertebrate CRIM1 in containing an insulin growth factor binding protein variant motif with unknown function. CHF was found to be induced in primary cell cultures of crayfish hematopoietic tissue (Hpt) cells (precursors of crayfish blood cells) after treatment with astakine 1. Silencing of CHF did not affect the renewal of Hpt cells in vitro, but induced apoptosis of Hpt cells. CHF is exclusively expressed in the blood cell lineage of crayfish (Hpt cells and blood cells), and in vivo RNA interference experiments show that knockdown of this gene results in severe loss of blood cells and a higher apoptotic rate in Hpt. Our data further suggest that crayfish CHF is critical for the survival of hemocytes and Hpt cells by preventing their apoptosis, thus it plays an important role in hemocyte homeostasis in crayfish. Our study of CHF may also shed light on the function of this untypical insulin growth factor binding protein motif located in the N-terminal of vertebrate CRIM1. PMID:21220699

Lin, Xionghui; Söderhäll, Kenneth; Söderhäll, Irene

2011-01-10

298

Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo.  

PubMed

Hematopoietic stem cells (HSC) are multipotent cells that reside in the bone marrow and replenish all adult hematopoietic lineages throughout the lifetime of the animal. While experimenting with staining of murine bone marrow cells with the vital dye, Hoechst 33342, we discovered that display of Hoechst fluorescence simultaneously at two emission wavelengths revealed a small and distinct subset of whole bone marrow cells that had phenotypic markers of multipotential HSC. These cells were shown in competitive repopulation experiments to contain the vast majority of HSC activity from murine bone marrow and to be enriched at least 1,000-fold for in vivo reconstitution activity. Further, these Hoechst-stained side population (SP) cells were shown to protect recipients from lethal irradiation at low cell doses, and to contribute to both lymphoid and myeloid lineages. The formation of the Hoechst SP profile was blocked when staining was performed in the presence of verapamil, indicating that the distinctly low staining pattern of the SP cells is due to a multidrug resistance protein (mdr) or mdr-like mediated efflux of the dye from HSC. The ability to block the Hoechst efflux activity also allowed us to use Hoechst to determine the DNA content of the SP cells. Between 1 and 3% of the HSC were shown to be in S-G2M. This also enabled the purification of the G0-G1 and S-G2M HSC had a reconstitution capacity equivalent to quiescent stem cells. These findings have implications for models of hematopoietic cell development and for the development of genetic therapies for diseases involving hematopoietic cells. PMID:8666936

Goodell, M A; Brose, K; Paradis, G; Conner, A S; Mulligan, R C

1996-04-01

299

Recognizing familial myeloid leukemia in adults  

PubMed Central

Germline testing for familial cases of myeloid leukemia in adults is becoming more common with the recognition of multiple genetic syndromes predisposing people to bone marrow disease. Currently, Clinical Laboratory Improvement Amendments approved testing exists for several myeloid leukemia predisposition syndromes: familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML), caused by mutations in RUNX1; familial AML with mutated CEBPA; familial myelodysplastic syndrome and acute leukemia with mutated GATA2; and the inherited bone marrow failure syndromes, including dyskeratosis congenita, a disease of abnormal telomere maintenance. With the recognition of additional families with a genetic component to their leukemia, new predisposition alleles will likely be identified. We highlight how to recognize and manage these cases as well as outline the characteristics of the major known syndromes. We look forward to future research increasing our understanding of the scope of inherited myeloid leukemia syndromes.

Nickels, Eric M.; Soodalter, Jesse; Churpek, Jane E.

2013-01-01

300

Recognizing familial myeloid leukemia in adults.  

PubMed

Germline testing for familial cases of myeloid leukemia in adults is becoming more common with the recognition of multiple genetic syndromes predisposing people to bone marrow disease. Currently, Clinical Laboratory Improvement Amendments approved testing exists for several myeloid leukemia predisposition syndromes: familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML), caused by mutations in RUNX1; familial AML with mutated CEBPA; familial myelodysplastic syndrome and acute leukemia with mutated GATA2; and the inherited bone marrow failure syndromes, including dyskeratosis congenita, a disease of abnormal telomere maintenance. With the recognition of additional families with a genetic component to their leukemia, new predisposition alleles will likely be identified. We highlight how to recognize and manage these cases as well as outline the characteristics of the major known syndromes. We look forward to future research increasing our understanding of the scope of inherited myeloid leukemia syndromes. PMID:23926458

Nickels, Eric M; Soodalter, Jesse; Churpek, Jane E; Godley, Lucy A

2013-08-01

301

5-Fluoro-2'-Deoxycytidine and Tetrahydrouridine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

2013-10-09

302

Induced pluripotent stem cells expressing elevated levels of sox-2, oct-4, and klf-4 are severely reduced in their differentiation from mesodermal to hematopoietic progenitor cells.  

PubMed

Induced pluripotent stem (iPS) cells have been generated from bone marrow (BM) hematopoietic progenitor cells by ectopic expression of Sox-2, Oct-4, and Klf-4 with the hope that they may differentiate more efficiently than embryonic stem (ES) cells in vitro into hematopoietic cell lineages because of their epigenetic memory. An in vitro culture system has been standardized to allow a quantitative assessment of the capacities of different ES, BM-derived iPS, and fibroblast-derived iPS cell lines developing to erythroid, myeloid, and lymphoid cell lineages. Surprisingly, the efficiency to differentiate BM-derived iPS cells to hematopoietic cells in vitro is severely reduced compared with ES cells and fibroblast-derived iPS cells. Undifferentiated as well as differentiated stages of the BM-derived iPS lines express elevated mRNA levels of the transcription factors Sox-2, Oct-4, and Klf-4 with which the iPS cells have been transduced. Overexpression of the transcription factors inhibits development of Flk-1(+) mesodermal to CD45(+) hematopoietic progenitors. The overexpression of Sox-2 appears to be inversely related to hematogenic potency. These results suggest that iPS cell generation with the aim of developing hematopoietic cells should be controlled and selected for low levels of transduced Sox-2, Oct-4, and Kfl-4 expression. PMID:21348597

Seiler, Katharina; Soroush Noghabi, Monireh; Karjalainen, Klaus; Hummel, Michael; Melchers, Fritz; Tsuneto, Motokazu

2011-02-24

303

Kinetics of hematopoiesis in bone marrow cultures from patients with chronic myeloid leukemia: effect of recombinant cytokines in dexter-type long-term cultures.  

PubMed

Chronic myeloid leukemia (CML) is a hematological neoplasia that results from the transformation of a hematopoietic stem cell. It is characterized by the expansion of the myeloid lineage, which results in the accumulation of mature and immature granulocytes in peripheral blood and bone marrow. However, when CML marrow cells are cultured in Dexter-type long-term cultures (LTMC) hematopoiesis is defective and can be sustained for only a few weeks. One possible explanation for the deficient growth of hematopoietic cells in CML LTMC is that some factors that act as key regulators of hematopoiesis are absent in this experimental system. Thus, we tested this hypothesis by adding recombinant cytokines to these cultures. As a first approach, we added recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF), rhGranulocyte-CSF (rhG-CSF) and rhErythropoietin (rhEPO); each factor was added individually once a week. Addition of rhGM-CSF and rhG-CSF resulted in a significant increase in the levels of nucleated cells and myeloid progenitors; the highest effects were seen in the presence of rhGM-CSF. Interestingly, such a cytokine also induced a significant decrease in the levels of erythroid progenitors. Recombinant hEPO had no significant effects on nucleated cells or myeloid progenitors, however, it induced a significant, although transient, increase in the levels of erythroid cells. The above results indicate that the hematopoietic regulators used here (rhGM-CSF, rhG-CSF and rhEPO) are capable of stimulating the growth of hematopoietic cells in LTMC from CML patients. Thus, this study demonstrates that it is, indeed, possible to manipulate CML LTMC by the addition of recombinant cytokines; this observation may be of particular relevance, since this in vitro experimental system has already been used as a method for purging of leukemic cells in autologous transplant settings. By using specific recombinant hematopoietic modulators it might be possible to make LTMC a more efficient system for such a clinical purpose. PMID:12745649

Luna-Bautista, Fernando; Sánchez-Valle, Elizabeth; Ayala-Sánchez, Manuel; Morales-Polanco, Manuel; Meillon-García, Luis; Benítez-Bribiesca, Luis; Mayani, Hector

2003-06-01

304

Immunotherapy with myeloid cells for tolerance induction  

PubMed Central

Purpose of review Understanding the interplay between myeloid dendritic cells and T cells under tolerogenic conditions, and whether their interactions induce the development of antigen-specific regulatory T cells (Tregs) is critical to uncover the mechanisms involved in the induction of indefinite allograft survival. Recent findings Myeloid dendritic cell–T-cell interactions are seminal events that determine the outcome of the immune response, and multiple in-vitro protocols suggest the generation of tolerogenic myeloid dendritic cells that modulate T-cell responses, and determine the outcome of the immune response to an allograft following adoptive transfer. We believe that identifying specific conditions that lead to the generation of tolerogenic myeloid dendritic cells and Tregs are critical for the manipulation the immune response towards the development of transplantation tolerance. Summary We summarize recent findings regarding specific culture conditions that generate tolerogenic myeloid dendritic cells that induce T-cell hyporesponsiveness and Treg development, and represents a novel immunotherapeutic approach to promote the induction of indefinite graft survival prolongation. The interpretations presented here illustrate that different mechanisms govern the generation tolerogenic myeloid dendritic cells, and we discuss the concomitant therapeutic implications.

Rodriguez-Garcia, Mercedes; Boros, Peter; Bromberg, Jonathan S.; Ochando, Jordi C.

2013-01-01

305

Hematopoietic Cell Regulation of Osteoblast Proliferation and Differentiation  

PubMed Central

The last several decades have revealed numerous interactions between cells of the hematopoietic lineage and osteoblasts (OBs) of the mesenchymal lineage. For example, OBs are important players in the hematopoietic stem cell (HSC) niche and OBs are known to impact osteoclast (OC) development. Thus, although much is known regarding the impact OBs have on hematopoietic cells, less is known about the impact of hematopoietic cells on OBs. Here we will review this reciprocal relationship: the effects of hematopoietic cells on OBs. Specifically, we will examine the impact of hematopoietic cells such as HSCs, lymphocytes, and megakaryocytes, as well as the hematopoietic cell–derived OCs on OB proliferation, differentiation, and function.

Bethel, Monique; Srour, Edward F.

2011-01-01

306

Lenalidomide, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

2013-09-16

307

Decitabine, Vorinostat, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

2013-06-17

308

Hematopoietic toxicity of regional radiation therapy. Correlations for combined modality therapy with systemic chemotherapy  

SciTech Connect

Using circulating granulocyte-monocyte precursor colony-forming units in culture (CFUc) numbers as a probe along with standard blood count (CBC), the authors have quantitatively examined the hematopoietic toxicity of conventionally fractionated radiation therapy (RT) when combined with concurrent systemic chemotherapy or when used alone. Among 20 patients with limited stage small cell lung cancer receiving systemic chemotherapy with cyclophosphamide, CCNU, and methotrexate, the addition of involved field chest RT resulted in increased hematopoietic toxicity as judged by increased need for platelet transfusion (P less than 0.05) and decreased frequency of measurable CFUc (P less than 0.04). Among 22 patients receiving regional radiotherapy alone consistent hematopoietic toxicity was also observed. This toxicity, although generally of only mild to moderate clinical significance, was detected earlier and to a greater degree in patients who required radiation to larger treatment volumes, who had significant amounts of bone marrow in the port, and who had a high percentage of cardiac output flowing through the port. These data suggest that the hematopoietic toxicity of regional radiotherapy may be additive to that of concurrent systemic chemotherapy and may occur more promptly and to a greater degree when treatment volumes are larger or incorporate increased amounts of marrow volume or cardiac output.

Abrams, R.A.; Lichter, A.S.; Bromer, R.H.; Minna, J.D.; Cohen, M.H.; Deisseroth, A.B.

1985-04-01

309

cDNA Cloning of a Human mRNA Preferentially Expressed in Hematopoietic Cells and with Homology to a GDP-Dissociation Inhibitor for the rho GTP Binding Proteins  

Microsoft Academic Search

We have identified the mRNA for a human gene, denoted D4, which is expressed at very high levels in hematopoietic cell lines and in normal cells of lymphoid and myeloid origin. The 1.5-kb transcript is absent or detectable only at low levels in nonhematopoietic tissues. D4 encodes a 201-amino acid protein with homology to rhoGDI, an inhibitor of GDP dissociation

Jean-Michel Lelias; Chaker N. Adra; Gerburg M. Wulf; Jean-Claude Guillemot; Mourad Khagad; Daniel Caput; Bing Lim

1993-01-01

310

Control of Both Myeloid Cell Infiltration and Angiogenesis by CCR1 Promotes Liver Cancer Metastasis Development in Mice12  

PubMed Central

Expression of the CC chemokine receptor 1 (CCR1) by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM) and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo) in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy.

Rodero, Mathieu Paul; Auvynet, Constance; Poupel, Lucie; Combadiere, Behazine; Combadiere, Christophe

2013-01-01

311

Precursor T-cell acute lymphoblastic leukemia presenting with bone marrow necrosis: a case report  

PubMed Central

Introduction Bone marrow necrosis is a clinicopathological condition diagnosed most often at postmortem examination, but it is also seen during the course of malignancy and is not always associated with a poor prognosis. The morphological features of bone marrow necrosis are disruption of the normal marrow architecture and necrosis of myeloid tissue and medullary stroma. Non-malignant conditions associated with bone marrow necrosis are sickle cell anemia, infections, drugs (sulfasalazine, interferon ?, all-trans retinoic acid, granulocyte colony-stimulating factor and fludarabine), disseminated intravascular coagulation, antiphospholipid antibody syndrome and acute graft versus host diseases. The malignant causes are leukemia, lymphoma and metastatic carcinomas. Herein we report the case of a patient with precursor T-cell acute lymphoblastic leukemia and bone marrow necrosis at initial presentation. Case presentation A 10-year-old Kurdish boy was presented with generalized bone pain and fever of 1 month’s duration which was associated with sweating, easy fatigability, nose bleeding, breathlessness and severe weight loss. On examination, we observed pallor, tachypnea, tachycardia, low blood pressure, fever, petechial hemorrhage, ecchymoses, tortuous dilated veins over the chest and upper part of abdomen, multiple small cervical lymph node enlargements, mildly enlarged spleen, palpable liver and gross abdominal distention. Blood analysis revealed pancytopenia and elevated lactate dehydrogenase and erythrocyte sedimentation rate. Imaging results showed mediastinal widening on a planar chest X-ray and diffuse focal infiltration of the axial bone marrow on magnetic resonance imaging of the lumbosacral vertebrae. Bone marrow aspiration and biopsy examination showed extensive bone marrow necrosis. Immunophenotyping analysis of the bone marrow biopsy confirmed T-cell acute lymphoblastic leukemia, as CD3 and terminal deoxynucleotidyl transferase markers were positive and CD10, CD20 and CD79a markers were negative. Conclusion The aggressive initial clinical presentation of our patient with huge mediastinal widening, development of superior vein cava syndrome and extensive bone marrow necrosis as initial signs made the diagnosis of the case difficult. The necrotic hematopoietic cells gave inconclusive results on the initial immunohistochemistry tests. The prognosis of bone marrow necrosis is better secondary to acute lymphoblastic leukemia in the pediatric age group compared with adults and those with underlying solid tumors. Despite the aggressive behavior at initial presentation, the patient responded to chemotherapy and necrosis disappeared at day 28 after the start of the therapeutic regimen.

2012-01-01

312

The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells  

PubMed Central

A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL down-regulates the B lymphoid kinase (Blk) gene through c-Myc in leukemia stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses human CML stem cells. Our results demonstrate the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers.

Zhang, Haojian; Peng, Cong; Hu, Yiguo; Li, Huawei; Sheng, Zhi; Chen, Yaoyu; Sullivan, Con; Cerny, Jan; Hutchinson, Lloyd; Higgins, Anne; Miron, Patricia; Zhang, Xueqing; Brehm, Michael; Li, Dongguang; Green, Michael R.; Li, Shaoguang

2012-01-01

313

Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation.  

PubMed

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a "difficult-to-manage" state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era. PMID:22937303

Uz, B; Bektas, O; Eliac?k, E; Goker, H; Erbilgin, Y; Sayitoglu, M; Sayinalp, N; Aksu, S; Buyukasik, Y; Ozcebe, O; Haznedaroglu, I C

2011-11-03

314

The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia  

PubMed Central

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.

Nestal de Moraes, Gabriela; Souza, Paloma Silva; Costas, Fernanda Casal de Faria; Vasconcelos, Flavia Cunha; Reis, Flaviana Ruade Souza; Maia, Raquel Ciuvalschi

2012-01-01

315

Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation  

PubMed Central

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a “difficult-to-manage” state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era.

Uz, B.; Bektas, O.; Eliac?k, E.; Goker, H.; Erbilgin, Y.; Sayitoglu, M.; Sayinalp, N.; Aksu, S.; Buyukasik, Y.; Ozcebe, O.; Haznedaroglu, I. C.

2011-01-01

316

Oblimersen, Cytarabine, and Daunorubicin in Treating Older Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2013-06-03

317

Expression profilings of 39 genes selected by ANOVA could separate precursors of murine dendritic cells and macrophages  

Microsoft Academic Search

Dendritic cells (DCs) and macrophages share some stages in the development and function of antigen presentation. But it is difficult to separate them from their precursors. We used one-way ANOVA (analysis of variances) on murine expression profilings of several hematopoietic cells associated with DCs and macrophages to find the genes with great differences across the cell groups. These groups were

Shixin Zhou; Yuqin Liu; Hong Bo; Xiaocui Bian; Xiaojun Xia; Changsheng Lin; Vincent Wai-Sun Wong; Zuhong Lu

2006-01-01

318

NPM1-mutated acute myeloid leukemia of monocytic or myeloid origin exhibit distinct immunophenotypes.  

PubMed

Acute myeloid leukemia with mutated nucleophosmin (NPM1m+AML) is a heterogeneous entity. We investigated whether NPM1m+AML with monocytic or myeloid differentiation have distinct immunophenotype. The study included 160 NPM1m+AMLpatients and 178 AML patients without NPM1 mutation and recurrent cytogenetic abnormality (NPM1wt-AML). We analyzed the immunophenotype by flow cytometry. NPM1 mutation was detected by PCR. Compared with NPM1wt-AML patients, NPM1m+AML patients showed higher positive rates of CD33 and CD9 and lower positive rates of CD34, HLA-DR, CD7, CD15 and CD117 (all P<0.05). HLA-DR, CD64, CD14, CD11b, CD15, CD4, CD9 and CD10 were higher (P<0.001) and CD117 was lower (P<0.01) in monocytic NPM1m+AML compared with myeloid NPM1m+AML. Similar rates of lymphoid antigen (CD19, CD2, and CD7) and myeloid antigen (CD13, CD33) positivity were detected in monocytic and myeloid NPM1m+AML. Compared with NPM1wt-AML, CD34 expression was lower both in myeloid and monocytic NPM1m+AML subgroups, although HLA-DR was lower in NPM1m+AML compared with NPM1wt-AML only in myeloid subgroup. Comparisons of NPM1m+AML and NPM1wt-AML showed no differences in monocyte-associated markers such as CD14 and CD11b in myeloid and monocytic subgroup. Myeloid NPM1m+AML correlated with the female gender (P=0.001), lower WBC counts (P=0.04) and higher WT1 transcripts (P=0.006) compared with monocytic NPM1m+AML.These results suggested monocytic and myeloid-derived NPM1m+AML exhibit distinct immunophenotypes. PMID:23601747

Liu, Yan-Rong; Zhu, Hong-Hu; Ruan, Guo-Rui; Qin, Ya-Zhen; Shi, Hong-Xia; Lai, Yue-Yun; Chang, Yan; Wang, Ya-Zhe; Lu, Dan; Hao, Le; Li, Jin-Lan; Li, Ling-Di; Jiang, Bin; Huang, Xiao-Jun

2013-04-16

319

Dominant role of oncogene dosage and absence of tumor suppressor activity in nras-driven hematopoietic transformation.  

PubMed

Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic Nras(G12D) in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased Nras(G12D) gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of Nras(G12D/G12D) hematopoietic cells. Modulating Nras(G12D) dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MAP-ERK kinase (MEK) inhibition. Furthermore, enforced WT N-Ras expression neither suppressed the growth of Nras-mutant cells nor inhibited myeloid transformation by exogenous Nras(G12D). Importantly, NRAS expression increased in human cancer cell lines with NRAS mutations. These data have therapeutic implications and support reconsidering the proposed tumor suppressor activity of WT Ras in other cancers. PMID:23733505

Xu, Jin; Haigis, Kevin M; Firestone, Ari J; McNerney, Megan E; Li, Qing; Davis, Elizabeth; Chen, Shann-Ching; Nakitandwe, Joy; Downing, James; Jacks, Tyler; Le Beau, Michelle M; Shannon, Kevin

2013-06-03

320

Characterization of G-protein alpha subunits in the Gq class: expression in murine tissues and in stromal and hematopoietic cell lines.  

PubMed Central

Murine G alpha 14 and G alpha 15 cDNAs encode distinct alpha subunits of heterotrimeric guanine nucleotide-binding proteins (G proteins). These alpha subunits are related to members of the Gq class and share certain sequence characteristics with G alpha q, G alpha 11, and G alpha 16, such as the absence of a pertussis toxin ADP-ribosylation site. G alpha 11 and G alpha q are ubiquitously expressed among murine tissues but G alpha 14 is predominantly expressed in spleen, lung, kidney, and testis whereas G alpha 15 is primarily restricted to hematopoietic lineages. Among hematopoietic cell lines, G alpha 11 mRNA is found in all cell lines tested, G alpha q is expressed widely but is not found in most T-cell lines, G alpha 15 is predominantly expressed in myeloid and B-cell lineages, and G alpha 14 is expressed in bone marrow adherent (stromal) cells, certain early myeloid cells, and progenitor B cells. Polyclonal antisera produced from synthetic peptides that correspond to two regions of G alpha 15 react with a protein of 42 kDa expressed in B-cell membranes and in Escherichia coli transformed with G alpha 15 cDNA. The expression patterns that were observed in mouse tissues and cell lines indicate that each of the alpha subunits in the Gq class may be involved in pertussis toxin-insensitive signal-transduction pathways that are fundamental to hematopoietic cell differentiation and function. Images

Wilkie, T M; Scherle, P A; Strathmann, M P; Slepak, V Z; Simon, M I

1991-01-01

321

Abnormalities of myeloid progenitor cells after "successful" bone marrow transplantation.  

PubMed Central

We studied recovery of peripheral blood- and bone marrow-derived myeloid progenitor cells (CFU-G,M) in 29 patients who received bone marrow transplants 2 mo to 8.5 yr previously. All patients had normal levels of peripheral blood neutrophils, normal bone marrow cellularity, and a normal myeloid-erythroid ratio. Both peripheral blood- and bone marrow-derived CFU-G,M were markedly reduced compared with normal controls and bone marrow donors [5 +/- 1/10(6) vs. 37 +/- 4/10(6) (P less than 0.001) and 23 +/- 5/2 x 10(5) vs. 170 +/- 21/2 x 10(5) (P less than 0.001)]. Five patients had no detectable CFU-G,M even when 10(6) bone marrow cels were plated. These abnormalities of CFU-G,M were unrelated to age, sex, diagnosis, conditioning regimen, dose of bone marrow cells transplanted, and presence or absence of graft-vs.-host disease. Patients who received either autotransplants or transplants from identical twins also had decreased or absent CFU-G,M indicating that allogeneic factors and posttransplant immune suppressor with methotrexate or corticosteroids were not major determinants of this abnormality. Co-culture of normal or donor peripheral blood or bone marrow mononuclear cells with recipients peripheral blood or bone marrow mononuclear cells, purified T cells, or serum failed to show any evidence of active CFU-G,M suppression. Furthermore, the abnormality of CFU-G,M could not be corrected by the addition of normal syngeneic (donor) hematopoietic cells or serum. Depletion of T-cells from recipient bone marrow by physical techniques resulted in marked increase in CFU-G,M (36 +/- 13 vs. 138 +/- 36; P less than 0.05). The abnormality could be reproduced in vitro by readdition of autologous T cells. In contrast to results with T cell depletion by physical techniques, T cell depletion with a monoclonal anti-T antibody (B7) and complement had no effect. These data indicate that most-transplant recipients have a marked abnormality in CFU-G,M when these cells are cultured in vitro. In at least some of these patients, the decreased cloning efficiency of CFU-G,M appears to be mediated by a suppressive effect of autologous T cells. Images

Li, S; Champlin, R; Fitchen, J H; Gale, R P

1985-01-01

322

A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification  

PubMed Central

The MLL-AF4 fusion gene is a hallmark genomic aberration in high-risk acute lymphoblastic leukemia in infants. Although it is well established that MLL-AF4 arises prenatally during human development, its effects on hematopoietic development in utero remain unexplored. We have created a human-specific cellular system to study early hemato-endothelial development in MLL-AF4-expressing human embryonic stem cells (hESCs). Functional studies, clonal analysis and gene expression profiling reveal that expression of MLL-AF4 in hESCs has a phenotypic, functional and gene expression impact. MLL-AF4 acts as a global transcriptional activator and a positive regulator of homeobox gene expression in hESCs. Functionally, MLL-AF4 enhances the specification of hemogenic precursors from hESCs but strongly impairs further hematopoietic commitment in favor of an endothelial cell fate. MLL-AF4 hESCs are transcriptionally primed to differentiate towards hemogenic precursors prone to endothelial maturation, as reflected by the marked upregulation of master genes associated to vascular-endothelial functions and early hematopoiesis. Furthermore, we report that MLL-AF4 expression is not sufficient to transform hESC-derived hematopoietic cells. This work illustrates how hESCs may provide unique insights into human development and further our understanding of how leukemic fusion genes, known to arise prenatally, regulate human embryonic hematopoietic specification.

Bueno, Clara; Montes, Rosa; Melen, Gustavo J; Ramos-Mejia, Veronica; Real, Pedro J; Ayllon, Veronica; Sanchez, Laura; Ligero, Gertrudis; Gutierrez-Aranda, Ivan; Fernandez, Agustin F; Fraga, Mario F; Moreno-Gimeno, Inmaculada; Burks, Deborah; del Carmen Plaza-Calonge, Maria; Rodriguez-Manzaneque, Juan C; Menendez, Pablo

2012-01-01

323

Inhibiting the palmitoylation/depalmitoylation cycle selectively reduces the growth of hematopoietic cells expressing oncogenic Nras  

PubMed Central

The palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-RasG12D formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Importantly, palmostatin B-mediated inhibition was selective for Nras mutant cells, and we mapped this activity to the hypervariable region. These data support the clinical development of depalmitoylation inhibitors as a novel class of rational therapeutics in hematologic malignancies with NRAS mutations.

Xu, Jin; Hedberg, Christian; Dekker, Frank J.; Li, Qing; Haigis, Kevin M.; Hwang, Eugene; Waldmann, Herbert

2012-01-01

324

FoxO3a Directs a Protective Autophagy Program in Hematopoietic Stem Cells  

PubMed Central

Blood production is ensured by rare self-renewing hematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here, we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy following ex vivo cytokine withdrawal and in vivo caloric restriction. We demonstrate that FoxO3a is critical to maintain a gene expression program that poise HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FoxO3a-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.

Warr, Matthew R.; Binnewies, Mikhail; Flach, Johanna; Reynaud, Damien; Garg, Trit; Malhotra, Ritu; Debnath, Jayanta; Passegue, Emmanuelle

2013-01-01

325

C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence  

PubMed Central

Summary In blood, transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver (FL) hematopoietic stem cells (HSCs). However, its function in adult HSCs has remained unknown. Here, using an inducible knockout model we found that C/EBPa deficient adult HSCs underwent a pronounced expansion with enhanced proliferation, characteristics resembling FL HSCs. Consistently, transcription profiling of C/EBPa deficient HSCs revealed a gene expression programme similar to FL HSCs. Moreover we observed that age-specific C/EBPa expression correlated with its inhibitory effect on HSC cell cycle. Mechanistically we identified N-Myc as C/EBPa downstream target, and loss of C/EBPa resulted in de-repression of N-Myc. Our data establish C/EBPa as a central determinant in the switch from fetal to adult HSCs.

Ye, Min; Zhang, Hong; Amabile, Giovanni; Yang, Henry; Staber, Philipp B.; Zhang, Pu; Levantini, Elena; Alberich-Jorda, Meritxell; Zhang, Junyan; Kawasaki, Akira; Tenen, Daniel G.

2013-01-01

326

Cytokines regulate postnatal hematopoietic stem cell expansion: opposing roles of thrombopoietin and LNK  

PubMed Central

The role of cytokines as regulators of hematopoietic stem cell (HSC) expansion remains elusive. Herein, we identify thrombopoietin (THPO) and the cytokine signaling inhibitor LNK, as opposing physiological regulators of HSC expansion. Lnk?/? HSCs continue to expand postnatally, up to 24-fold above normal by 6 mo of age. Within the stem cell compartment, this expansion is highly selective for self-renewing long-term HSCs (LT-HSCs), which show enhanced THPO responsiveness. Lnk?/? HSC expansion is dependent on THPO, and 12-wk-old Lnk?/?Thpo?/? mice have 65-fold fewer LT-HSCs than Lnk?/? mice. Expansions of multiple myeloid, but not lymphoid, progenitors in Lnk?/? mice also proved THPO-dependent.

Buza-Vidas, Natalija; Antonchuk, Jennifer; Qian, Hong; Mansson, Robert; Luc, Sidinh; Zandi, Sasan; Anderson, Kristina; Takaki, Satoshi; Nygren, Jens M.; Jensen, Christina T.; Jacobsen, Sten Eirik W.

2006-01-01

327

Radioimmunotherapy for hematopoietic cell transplantation.  

PubMed

Radioimmunotherapy (RIT) represents an attractive strategy to deliver radiation selectively to tumor and other target organs while minimizing toxicity to normal tissues. RIT with ?-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of conditioning before hematopoietic cell transplantation (HCT) in leukemia. Similarly, RIT directed against CD20 has shown promise in the setting of autologous and allogeneic HCT for B-cell lymphomas. ?-particle immunotherapy with isotopes such as bismuth-213, actinium-225 and astatinine-211 offers the possibility of more selective and efficient killing of target cells while sparing the surrounding normal cells. Pretargeting strategies may further improve target:normal organ dose ratios. While RIT has demonstrated significant antitumor activity, ultimately, randomized studies will be required to determine if conditioning regimens that include this therapeutic modality can improve patient outcomes after HCT. PMID:23557421

Jurcic, Joseph G

2013-04-01

328

Hematopoietic stem cell fate is established by the Notch-Runx pathway  

PubMed Central

Identifying the molecular pathways regulating hematopoietic stem cell (HSC) specification, self-renewal, and expansion remains a fundamental goal of both basic and clinical biology. Here, we analyzed the effects of Notch signaling on HSC number during zebrafish development and adulthood, defining a critical pathway for stem cell specification. The Notch signaling mutant mind bomb displays normal embryonic hematopoiesis but fails to specify adult HSCs. Surprisingly, transient Notch activation during embryogenesis via an inducible transgenic system led to a Runx1-dependent expansion of HSCs in the aorta-gonad-mesonephros (AGM) region. In irradiated adults, Notch activity induced runx1 gene expression and increased multilineage hematopoietic precursor cells approximately threefold in the marrow. This increase was followed by the accelerated recovery of all the mature blood cell lineages. These data define the Notch–Runx pathway as critical for the developmental specification of HSC fate and the subsequent homeostasis of HSC number, thus providing a mechanism for amplifying stem cells in vivo.

Burns, Caroline Erter; Traver, David; Mayhall, Elizabeth; Shepard, Jennifer L.; Zon, Leonard I.

2005-01-01

329

Tipifarnib in Treating Patients With Acute Myeloid Leukemia in Remission  

ClinicalTrials.gov

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts in Transformation

2013-10-07

330

Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2013-10-07

331

What's New in Chronic Myeloid Leukemia Research and Treatment?  

MedlinePLUS

... Topic Additional resources for chronic myeloid leukemia What`s new in chronic myeloid leukemia research and treatment? Studies ... such as cyclosporine or hydroxychloroquine, with a TKI. New drugs for CML Because researchers now know the ...

332

What's New in Adult Acute Myeloid Leukemia Research and Treatment?  

MedlinePLUS

... Topic Additional resources for acute myeloid leukemia What’s new in acute myeloid leukemia research and treatment? Researchers ... against AML (see below). Gene expression profiling This new lab technique is being studied to help identify ...

333

Hematopoietic microenvironment. Origin, lineage, and transplantability of the stromal cells in long-term bone marrow cultures from chimeric mice  

SciTech Connect

Studies of bone marrow transplant patients have suggested that the stromal cells of the in vitro hematopoietic microenvironment are transplantable into conditioned recipients. Moreover, in patients with myeloproliferative disorders, all of the stromal cells, which include presumptive endothelial cells, appear to be derived from hematopoietic precursors. To confirm these findings, we have constructed two chimeric mouse models: (a) traditional radiation chimeras, and (b) fetal chimeras, produced by placental injection of bone marrow into genetically anemic Wx/Wv fetuses, a technique that essentially precludes engraftment of nonhematopoietic cells. Using two-color indirect immunofluorescence, the stromal cells in long-term bone marrow culture derived from these chimeras were analyzed for donor or host origin by strain-specific H-2 antigens, and for cell lineage by a variety of other specific markers. 75-95% of the stromal cells were shown to be hematopoietic cells of the monocyte-macrophage lineage, based upon donor origin, phagocytosis, and expression of specific hematopoietic surface antigens. The remaining 5-25% of the stromal cells were exclusively host in origin. Apart from occasional fat cells, these cells uniformly expressed collagen type IV, laminin, and a surface antigen associated with endothelial cells. Since these endothelial-like cells are not transplantable into radiation or fetal chimeras, they are not derived from hematopoietic stem cells. The contrast between our findings and human studies suggests either unexpected species differences in the origin of stromal lineages or limitations in the previous methodology used to detect nonhematopoietic stromal cells.

Perkins, S.; Fleischman, R.A.

1988-04-01

334

Hematopoietic Stem Cell Identification and Isolation.  

National Technical Information Service (NTIS)

The present invention relates to methods of identifying, collecting and isolating hematopoietic stem cells (HSCs) and compositions of purified HSCs. Specifically, the present invention provides methods of isolating and purifying CD150.sup.+ HSCs, CD48.sup...

M. J. Kiel O. H. Yilmaz S. Morrison T. Iwashita

2004-01-01

335

Hematopoietic miR155 Deficiency Enhances Atherosclerosis and Decreases Plaque Stability in Hyperlipidemic Mice  

PubMed Central

microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory mediators. Although miR155 is considered to be a pro-inflammatory microRNA, in vitro reports show anti-inflammatory effects in lipid-loaded cells. In this study we examined the role of miR155 in atherosclerosis in vivo using bone marrow transplantation from miR155 deficient or wildtype mice to hyperlipidemic mice. Hematopoietic deficiency of miR155 enhanced atherosclerotic plaque development and decreased plaque stability, as evidenced by increased myeloid inflammatory cell recruitment to the plaque. The increased inflammatory state was mirrored by a decrease in circulating CD4+CD25+FoxP3+ regulatory T cells, and an increase in granulocytes (CD11b+Ly6G+) in blood of miR155?/? transplanted mice. Moreover, we show for the first time a crucial role of miR155 in monocyte subset differentiation, since hematopoietic deficiency of miR155 increases the ‘inflammatory’ monocyte subset (CD11b+Ly6G?Ly6Chi) and reduces ‘resident’ monocytes (CD11b+Ly6G?Ly6Clow) in the circulation. Furthermore, cytokine production by resident peritoneal macrophages of miR155?/? transplanted hyperlipidemic mice was skewed towards a more pro-inflammatory state since anti-inflammatory IL-10 production was reduced. In conclusion, in this hyperlipidemic mouse model miR155 acts as an anti-inflammatory, atheroprotective microRNA. Additionally, besides a known role in lymphoid cell development, we show a crucial role of miR155 in myeloid lineage differentiation.

Donners, Marjo M. P. C.; Wolfs, Ine M. J.; Stoger, Lauran J.; van der Vorst, Emiel P. C.; Pottgens, Chantal C. H.; Heymans, Stephane; Schroen, Blanche; Gijbels, Marion J. J.; de Winther, Menno P. J.

2012-01-01

336

[Haploidentical hematopoietic stem cell transplantation for the treatment of severe aplastic anemia in children].  

PubMed

This study was purposed to assess the effectiveness of haploidentical hematopoietic stem cell transplantation (HSCT) without in vitro T cell depletion for the treatment of severe aplastic anemia (SAA) in children. Two children with SAA/very SAA (VSAA) received T cell-depleted HSCT from their fathers with 2 loci mismatched in our center between October 2010 and March 2013. During 4 months after onset, both failed in treatment of cyclosporine (CsA)+ granulocyte colony stimulating factor (G-CSF), had active or serious infections, were transfusion dependent and lacked HLA-identical sibling donors and unrelated donors. The conditioning regimen before HSCT included fludarabine, cyclophosphamide and thymoglobulin. The source of grafts was a combination of G-CSF mobilized peripheral blood hematopoietic stem cells and BM. The recipients received CsA, mycophenolate mofetil (MMF) and short-term MTX for GVHD prophylaxis. Both children with SAA achieved 100% donor myeloid engraftment. Neutrophil engraftment occurred at day 12 and day 18 after transplant respectively. Platelet engraftment occurred at day 17 and day 26 after transplantion respectively. Two patients all developed grade I acute graft versus host disease (GVHD), one of which evolved into chronic limited GVHD well-controlled. Both have survived for two years after transplantation with 100% donor myeloid engraftment and effective lymphoid reconstitution. In conclusion, these limited cases suggest that haploidentical HSCT for children with SAA without a HLA-identical sibling donor and unrelated donor may be feasible. Further prospective clinical study is required to increase the overall survival (OS) by decreasing GVHD while maintaining stable engraftment. PMID:23998598

Liu, Ying; Tang, Suo-Qin; Huang, Wen-Rong; Li, Hong-Hua; Zhao, Yu; Bo, Jian; Zhang, Ning; Wang, Fang; Yu, Li

2013-07-01

337

Hematopoietic miR155 deficiency enhances atherosclerosis and decreases plaque stability in hyperlipidemic mice.  

PubMed

microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory mediators. Although miR155 is considered to be a pro-inflammatory microRNA, in vitro reports show anti-inflammatory effects in lipid-loaded cells. In this study we examined the role of miR155 in atherosclerosis in vivo using bone marrow transplantation from miR155 deficient or wildtype mice to hyperlipidemic mice. Hematopoietic deficiency of miR155 enhanced atherosclerotic plaque development and decreased plaque stability, as evidenced by increased myeloid inflammatory cell recruitment to the plaque. The increased inflammatory state was mirrored by a decrease in circulating CD4(+)CD25(+)FoxP3(+) regulatory T cells, and an increase in granulocytes (CD11b(+)Ly6G(+)) in blood of miR155(-/-) transplanted mice. Moreover, we show for the first time a crucial role of miR155 in monocyte subset differentiation, since hematopoietic deficiency of miR155 increases the 'inflammatory' monocyte subset (CD11b(+)Ly6G(-)Ly6C(hi)) and reduces 'resident' monocytes (CD11b(+)Ly6G(-)Ly6C(low)) in the circulation. Furthermore, cytokine production by resident peritoneal macrophages of miR155(-/-) transplanted hyperlipidemic mice was skewed towards a more pro-inflammatory state since anti-inflammatory IL-10 production was reduced. In conclusion, in this hyperlipidemic mouse model miR155 acts as an anti-inflammatory, atheroprotective microRNA. Additionally, besides a known role in lymphoid cell development, we show a crucial role of miR155 in myeloid lineage differentiation. PMID:22558252

Donners, Marjo M P C; Wolfs, Ine M J; Stöger, Lauran J; van der Vorst, Emiel P C; Pöttgens, Chantal C H; Heymans, Stephane; Schroen, Blanche; Gijbels, Marion J J; de Winther, Menno P J

2012-04-25

338

Differentiation of hematopoietic stem cells in irradiated mouse thymic lobes. Kinetics and phenotype of progeny  

SciTech Connect

To define cell populations which participate in the very early stages of T cell development in the mouse thymus, we enriched hematopoietic stem cells from mouse bone marrow and injected them into thymic lobes of irradiated Ly-5 congenic recipients. The progeny of the stem cells were identified and their phenotypes were determined by two-color flow cytometry for the expression of various cell surface differentiation Ag during the course of their subsequent intrathymic development. The majority of the differentiation which occurred in the first 10 days after intrathymic cell transfer was myeloid in nature; hence, this study demonstrates that the irradiated thymus is not strictly selective for T cell development. Further, the maximum rate of T cell development was observed after intrathymic injection of 200 stem cells. Donor-derived cells which did not express Ag characteristic of the myeloid lineage could be detected and their phenotypes could be determined by flow cytometry as early as 7 days after intrathymic injection. At this time, the cells were still very similar phenotypically to the bone marrow hematopoietic stem cells. Exceptions to this were the expression of stem cell Ag 2 and a decrease in the level of MHC class I Ag expression. After 9 days, the donor-derived cells expressed high levels of the Thy-1 Ag and proceeded to change in cell surface phenotype as differentiation continued. These cell phenotypes are described for the time frame ending 18 days after injection, when most donor-derived cells were phenotypically small CD4+ CD8+ (double-positive) thymocytes.

Spangrude, G.J.; Scollay, R. (Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria (Australia))

1990-12-01

339

Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice  

PubMed Central

Transgenic expression of the abnormal products of acute myeloid leukemia–associated (AML-associated) primary chromosomal translocations in hematopoietic stem/progenitor cells initiates leukemogenesis in mice, yet additional mutations are needed for leukemia development. We report here aberrant expression of PR domain containing 16 (PRDM16) in AML cells with either translocations of 1p36 or normal karyotype. These carried, respectively, relatively high prevalence of mutations in the TP53 tumor suppressor gene and in the nucleophosmin (NPM) gene, which regulates p53. Two protein isoforms are expressed from PRDM16, which differ in the presence or absence of the PR domain. Overexpression of the short isoform, sPRDM16, in mouse bone marrow induced AML with full penetrance, but only in the absence of p53. The mouse leukemias were characterized by multilineage cellular abnormalities and megakaryocyte dysplasia, a common feature of human AMLs with 1p36 translocations or NPM mutations. Overexpression of sPRDM16 increased the pool of HSCs in vivo, and in vitro blocked myeloid differentiation and prolonged progenitor life span. Loss of p53 augmented the effects of sPRDM16 on stem cell number and induced immortalization of progenitors. Thus, overexpression of sPRDM16 induces abnormal growth of stem cells and progenitors and cooperates with disruption of the p53 pathway in the induction of myeloid leukemia.

Shing, Danielle C.; Trubia, Maurizio; Marchesi, Francesco; Radaelli, Enrico; Belloni, Elena; Tapinassi, Cinzia; Scanziani, Eugenio; Mecucci, Cristina; Crescenzi, Barbara; Lahortiga, Idoya; Odero, Maria D.; Zardo, Giuseppe; Gruszka, Alicja; Minucci, Saverio; Di Fiore, Pier Paolo; Pelicci, Pier Giuseppe

2007-01-01

340

Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia.  

PubMed

Nur77 (NR4A1) and Nor-1 (NR4A3) are highly homologous orphan nuclear receptors that regulate the transcription of overlapping target genes. The transcriptional activity of both proteins is regulated in a ligand-independent manner by cell- and stimulus-specific gene induction and protein phosphorylation. Nor-1 and Nur77 have been implicated in a variety of cellular processes, including the transduction of hormonal, inflammatory, mitogenic, apoptotic and differentiative signals. Cellular responses to these proteins suggest that they may function as homeostatic regulators of proliferation, apoptosis and differentiation, and thus may regulate cellular susceptibility to tumorigenesis. Their physiological functions, however, remain poorly understood. Here we describe a previously unsuspected function of Nor-1 and Nur77-as critical tumor suppressors of myeloid leukemogenesis. The abrogation of these proteins in mice led to rapidly lethal acute myeloid leukemia (AML), involving abnormal expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, decreased expression of the AP-1 transcription factors JunB and c-Jun and defective extrinsic apoptotic (Fas-L and TRAIL) signaling. We found that downregulation of NR4A3 ( NOR-1 ) and NR4A1 ( NUR77 ) was a common feature in leukemic blasts from human AML patients, irrespective of karyotype. Thus Nor-1 and Nur77 may provide potential targets for therapeutic intervention in AML. PMID:17515897

Mullican, Shannon E; Zhang, Shuo; Konopleva, Marina; Ruvolo, Vivian; Andreeff, Michael; Milbrandt, Jeffrey; Conneely, Orla M

2007-05-21

341

CD 33 as a target of therapy in acute myeloid leukemia: current status and future perspectives.  

PubMed

CD 33 is a myeloid cell surface antigen that is expressed on blast cells in acute myeloid leukemia (AML) in a majority of all patients regardless of age or subtype of disease. The antigen is also expressed on leukemic stem cells in many cases, but is not expressed on normal hematopoietic stem cells. In an attempt to improve therapy in AML, a CD 33-targeted drug has been developed. The drug, gemtucumab ozogamicin (GO; Mylotarg), consists of a humanized CD 33 antibody (hP 67.6), a pH-dependent linker, and a highly potent chemotherapy agent, calicheamicin 1,2,-dimethyl hydrazine dichloride. Based on its clinical activity, GO has been approved for application in chemotherapy-refractory AML in various countries and is effective as a mono-substance as well as in combination with conventional chemotherapy. However, despite high efficacy and a certain specificity for leukemic (as opposed to normal) stem cells, the drug does not work in all patients, and can produce significant side-effects, including veno-occlusive disease (VOD), especially in patients who undergo stem cell transplantation. These side-effects have to be balanced against the benefit of GO therapy in patients with relapsed or refractory AML. PMID:16085551

Sperr, Wolfgang R; Florian, Stefan; Hauswirth, Alexander W; Valent, Peter

2005-08-01

342

DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia  

PubMed Central

Background Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required. Methodology/Principal Findings We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients. Conclusions/Significance Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature.

Alvarez, Sara; Suela, Javier; Valencia, Ana; Fernandez, Agustin; Wunderlich, Mark; Agirre, Xabier; Prosper, Felipe; Martin-Subero, Jose Ignacio; Maiques, Alba; Acquadro, Francesco; Rodriguez Perales, Sandra; Calasanz, Maria Jose; Roman-Gomez, Jose; Siebert, Reiner; Mulloy, James C.; Cervera, Jose; Sanz, Miguel Angel; Esteller, Manel; Cigudosa, Juan C.

2010-01-01

343

CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia.  

PubMed

The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival. PMID:23744585

Green, Margaret L; Leisenring, Wendy M; Xie, Hu; Walter, Roland B; Mielcarek, Marco; Sandmaier, Brenda M; Riddell, Stanley R; Boeckh, Michael

2013-06-06

344

Management of extramedullary leukemia as a presentation of acute myeloid leukemia.  

PubMed

Extramedullary involvement is considered to be an uncommon presentation of acute myeloid leukemia (AML), although some data suggest it may be present in up to 30% of patients. Extra-medullary involvement by AML can present in a variety of clinical manifestations, most notably in the form of myeloid sarcoma, leukemia cutis, and central nervous system involvement. Each presents a unique clinical scenario in terms of symptoms and management. Extramedullary disease in any form presenting without evidence of bone marrow disease is still considered evidence of systemic disease and is usually treated as such. Most commonly, extramedullary disease presents concurrently with bone marrow disease, and although it may require additional local therapy in the form of intrathecal chemotherapy or radiation, the principles of systemic treatment remain unchanged. The prognostic impact of extramedullary disease is unclear. Specifically, whether hematopoietic stem cell transplantation should be considered in first remission irrespective of other prognostic factors has not been established. Patients who undergo transplantation have similar outcomes as patients without extramedullary disease, although they do have a higher rate of extramedullary relapse. More research is needed to define the molecular basis for extramedullary disease, its prognostic impact, and optimal management. PMID:22956813

Slomowitz, Samuel J; Shami, Paul J

2012-09-01

345

Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia.  

PubMed

We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1(+)) as well as markers of the B-cell lineage (B220(+)). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX-induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets. PMID:18388181

Jankovic, Dragana; Gorello, Paolo; Liu, Ting; Ehret, Sabire; La Starza, Roberta; Desjobert, Cecile; Baty, Florent; Brutsche, Martin; Jayaraman, Padma-Sheila; Santoro, Alessandra; Mecucci, Christina; Schwaller, Juerg

2008-04-03

346

Stem Cell Plasticity in the Hematopoietic System  

Microsoft Academic Search

Bone marrow (BM) contains hematopoietic stem cells, which differentiate into all mature blood cells, and marrow stromal cells\\u000a that provide the microenvironment for hematopoietic stem\\/progenitor cells along with the capability to differentiate into\\u000a mature cells of multiple mesenchymal tissues including fat, bone, and cartilage. Recent studies indicate that adult BM also\\u000a contains cells that can differentiate into nonhematopoietic cells of

Toshio Heike; Tatsutoshi Nakahata

2004-01-01

347

Cell Death in the Hematopoietic System  

Microsoft Academic Search

The mammalian hematopoietic system is prodigious: billions of blood cells are generated every day to maintain the supply of\\u000a oxygen to the tissues, repair damaged vasculature, and resist infection. It is becoming increasingly clear that the intrinsic\\u000a apoptosis pathway, under the control of the Bcl-2 family of proteins, plays many essential roles in the development and function\\u000a of hematopoietic cells

Emma C. Josefsson; Benjamin T. Kile

348

Dynamic transcriptomes of human myeloid leukemia cells.  

PubMed

To identify the mechanisms controlling chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) in humans, we analyzed genome-wide transcription dynamics in three myeloid leukemia cell lines (K562, HL-60, and THP1) using high-throughput sequencing technology. Using KEGG analysis, we found that the ERK/MAPK, JAK-STAT and ErbB pathways promoted proliferation and metabolism in CML. However, in AML, differentiation and apoptosis blocking resulted in the accumulation of blast cells in marrow. In addition, each cell type had unique characteristics. K562 cells are an ideal model for studying erythroid differentiation and globin gene expression. The chemokine signaling pathway and Fc gamma R-mediated phagocytosis were markedly upregulated in HL-60 cells. In THP1 cells, highly expressed genes ensured strong phagocytosis by monocytes. Further, we provide a new insight into myeloid development. The abundant data sets and well-defined analysis methods will provide a resource and strategy for further investigation of myeloid leukemia. PMID:23806289

Wang, Hai; Hu, Haiyan; Zhang, Qian; Yang, Yadong; Li, Yanming; Hu, Yang; Ruan, Xiuyan; Yang, Yaran; Zhang, Zhaojun; Shu, Chang; Yan, Jiangwei; Wakeland, Edward K; Li, Quanzhen; Hu, Songnian; Fang, Xiangdong

2013-06-24

349

AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2013-09-24

350

Preferential Langerhans cell differentiation from CD34+ precursors upon introduction of ABCG2 (BCRP)  

Microsoft Academic Search

Epidermal Langerhans cells (LC) and dermal interstitial dendritic cells (IDC) were found to express the ATP-binding cassette (ABC) transporter breast cancer resistance protein (BCRP; ABCG2). Also, low BCRP expression was present on CD34+ blood DC precursors and expression was increased upon their differentiation to LC. The CD34+ acute myeloid leukemia-derived DC cell line MUTZ3 can be cultured into LC or

Rieneke van de Ven; Jelle J Lindenberg; Anneke W Reurs; Rik J Scheper; George L Scheffer; Tanja D de Gruijl; TD de Gruijl

2012-01-01

351

TGF? restores hematopoietic homeostasis after myelosuppressive chemotherapy  

PubMed Central

Myelosuppression is a life-threatening complication of antineoplastic therapy, but treatment is restricted to a few cytokines with unilineage hematopoietic activity. Although hematopoietic stem cells (HSCs) are predominantly quiescent during homeostasis, they are rapidly recruited into cell cycle by stresses, including myelosuppressive chemotherapy. Factors that induce HSCs to proliferate during stress have been characterized, but it is not known how HSC quiescence is then reestablished. In this study, we show that TGF? signaling is transiently activated in hematopoietic stem and progenitor cells (HSPCs) during hematopoietic regeneration. Blockade of TGF? signaling after chemotherapy accelerates hematopoietic reconstitution and delays the return of cycling HSCs to quiescence. In contrast, TGF? blockade during homeostasis fails to induce cycling of HSPCs. We identified the cyclin-dependent kinase inhibitor Cdkn1c (p57) as a key downstream mediator of TGF? during regeneration because the recovery of chimeric mice, incapable of expressing p57 in HSPCs, phenocopies blockade of TGF? signaling after chemotherapy. This study demonstrates that context-dependent activation of TGF? signaling is central to an unrecognized counterregulatory mechanism that promotes homeostasis once hematopoiesis has sufficiently recovered from myelosuppressive chemotherapy. These results open the door to new, potentially superior, approaches to promote multilineage hematopoietic recovery by blocking the TGF? signaling that dampens regeneration.

Brenet, Fabienne; Kermani, Pouneh; Spektor, Roman; Rafii, Shahin

2013-01-01

352

Focal adhesion kinase splice variants maintain primitive acute myeloid leukemia cells through altered Wnt signaling.  

PubMed

Focal adhesion kinase (FAK) activity contributes to many advanced cancer phenotypes, but little is known about its role in human acute myeloid leukemia (AML). Here, we show that FAK splice variants are abnormally expressed in the primitive leukemic cells of poor prognosis AML patients. In the CD34(+) 38(-) 123(+) long-term culture-initiating cell-enriched leukemic cells of these patients, FAK upregulates expression of Frizzled-4 and phosphorylates Pyk2 to enable the required association of Pyk2 with the Wnt5a/Frizzled-4/LRP5 endocytosis complex and downstream activation of ?-catenin, thereby replacing the Wnt3a-controlled canonical pathway used by normal hematopoietic stem cells. Transduction of primitive normal human hematopoietic cells with FAK splice variants induces a marked increase in their clonogenic activity and signaling via the Wnt5a-controlled canonical pathway. Targeting FAK or ?-catenin efficiently eradicates primitive leukemic cells in vitro suggesting that FAK could be a useful therapeutic target for improved treatment of poor prognosis AML cases. PMID:22714993

Despeaux, Mathieu; Chicanne, Gaëtan; Rouer, Evelyne; De Toni-Costes, Fabienne; Bertrand, Jessica; Mansat-De Mas, Véronique; Vergnolle, Nathalie; Eaves, Connie; Payrastre, Bernard; Girault, Jean-Antoine; Racaud-Sultan, Claire

2012-08-01

353

MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy  

PubMed Central

A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20–30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these ‘sub-haploinsufficient’ cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies. DOI: http://dx.doi.org/10.7554/eLife.00825.001

Heinrichs, Stefan; Conover, Lillian F; Bueso-Ramos, Carlos E; Kilpivaara, Outi; Stevenson, Kristen; Neuberg, Donna; Loh, Mignon L; Wu, Wen-Shu; Rodig, Scott J; Garcia-Manero, Guillermo; Kantarjian, Hagop M; Look, A Thomas

2013-01-01

354

MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy.  

PubMed

A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these 'sub-haploinsufficient' cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies. DOI:http://dx.doi.org/10.7554/eLife.00825.001. PMID:23878725

Heinrichs, Stefan; Conover, Lillian F; Bueso-Ramos, Carlos E; Kilpivaara, Outi; Stevenson, Kristen; Neuberg, Donna; Loh, Mignon L; Wu, Wen-Shu; Rodig, Scott J; Garcia-Manero, Guillermo; Kantarjian, Hagop M; Look, A Thomas

2013-07-16

355

Myeloid Sarcoma: Clinical and Morphologic Criteria Useful for Diagnosis  

Microsoft Academic Search

Extramedullary accumulation of myeloblasts or immature myeloid cells form tumors called myeloid sarcoma in the WHO classification. Such tumors develop in lymphoid organs, bone (skull, orbit, etc.), skin, soft tissue, various mucosae and organs, and the CNS. They may precede or occur concurrently with acute myeloid leukemia, or reveal blastic transformation of chronic myeloproliferative disorders or myelodysplastic syndromes. They may

J. Audouin; E. Comperat; A. Le Tourneau; S. Camilleri-Broët; C. Adida; T. Molina; J. Diebold

2003-01-01

356

Progenitor cell hyperplasia with rare development of myeloid leukemia in interleukin 11 bone marrow chimeras  

PubMed Central

Post 5-fluorouracil-treated murine bone marrow cells infected with a recombinant retrovirus (murine stem cell virus-interleukin 11 [MSCV-IL- 11]) bearing a human IL-11 gene were transplanted into lethally irradiated syngeneic mice. Analysis of proviral integration sites in DNA prepared from hematopoietic tissues and purified cell populations of long-term reconstituted primary and secondary recipients demonstrated polyclonal engraftment by multipotential stem cells. High levels (100-1,500 U/ml) of IL-11 were detected in the plasma of the MSCV-IL-11 mice. Systemic effects of chronic IL-11 exposure included loss of body fat, thymus atrophy, some alterations in plasma protein levels, frequent inflammation of the eyelids, and often a hyperactive state. A sustained rise in peripheral platelet levels (approximately 1.5-fold) was seen throughout the observation period (4-17 wk). No changes were observed in the total number of circulating leukocytes in the majority of the transplanted animals (including 10 primary and 18 secondary recipients) despite a > 20-fold elevation in myeloid progenitor cell content in the spleen. The exceptions were members of one transplant pedigree which presented with myeloid leukemia during the secondary transplant phase. A clonal origin of the disease was determined, with significant expansion of the MSCV-IL-11-marked clone having occurred in the spleen of the primary host. Culturing of leukemic spleen cells from a quaternary recipient led to the establishment of a permanent cell line (denoted PGMD1). IL-11-producing PGMD1 myeloid leukemic cells are dependent on IL-3 for continuous growth in vitro and they differentiate into granulocytes and macrophages in response to granulocyte/macrophage colony-stimulating factor. The inability of autogenously produced IL-11 to support autonomous growth of PGMD1 cells argues against a mechanism of transformation involving a classical autocrine loop.

1993-01-01

357

Identification of Desirable Precursor Properties for Solution Precursor Plasma Spray  

NASA Astrophysics Data System (ADS)

In solution precursor plasma spray chemical precursor solutions are injected into a standard plasma torch and the final material is formed and deposited in a single step. This process has several attractive features, including the ability to rapidly explore new compositions and to form amorphous and metastable phases from molecularly mixed precursors. Challenges include: (a) moderate deposition rates due to the need to evaporate the precursor solvent, (b) dealing on a case by case basis with precursor characteristics that influence the spray process (viscosity, endothermic and exothermic reactions, the sequence of physical states through which the precursor passes before attaining the final state, etc.). Desirable precursor properties were identified by comparing an effective precursor for yttria-stabilized zirconia with four less effective candidate precursors for MgO:Y2O3. The critical parameters identified were a lack of major endothermic events during precursor decomposition and highly dense resultant particles.

Muoto, Chigozie K.; Jordan, Eric H.; Gell, Maurice; Aindow, Mark

2011-06-01

358

Chronic suppression of angiogenesis following radiation exposure is independent of hematopoietic reconstitution.  

PubMed

Radiation can potentially suppress neovascularization by inhibiting the incorporation of hematopoietic precursors as well as damaging mature endothelial cells. The purpose of these studies was to quantify the effect of radiation on angiogenesis and to examine the relationship between bone marrow reconstitution and neovascularization. Immune competent, severe combined immunodeficient, RAG1-deficient, and green fluorescence protein transgenic mice in the C57 genetic background, as well as the highly angiogenic 129S1/SvlmJ strain of mice, underwent whole-body or localized exposure to radiation. The hematopoietic systems in the irradiated recipients were restored by bone marrow transfer. Hematopoietic reconstitution was assessed by doing complete blood counts. Angiogenesis was induced in the mouse cornea using 80 ng of purified basic fibroblast growth factor, and the neovascular response was quantified using a slit lamp biomicroscope. Following whole-body exposure and bone marrow transplantation, the hematopoietic system was successfully reconstituted over time, but the corneal angiogenic response was permanently and significantly blunted up to 66%. Localized exposure of the eyes to radiation suppressed corneal angiogenesis comparably to whole-body exposure. Whole-body irradiation with ocular shielding induced bone marrow suppression but did not inhibit corneal neovascularization. In mice exposed to radiation before tumor implantation, the reduced local angiogenic response correlated with significantly reduced growth of tumor cells in vivo. These results indicate that bone marrow suppression does not suppress neovascularization in the mouse cornea and that although hematopoietic stem cells can readily reconstitute peripheral blood, they do not restore a local radiation-induced deficit in neovascular response. PMID:17332332

Udagawa, Taturo; Birsner, Amy E; Wood, Mark; D'Amato, Robert J

2007-03-01

359

Vaccines as consolidation therapy for myeloid leukemia  

PubMed Central

Immunotherapy for myeloid leukemias remains a cornerstone in the management of this highly aggressive group of malignancies. Allogeneic (allo) stem cell transplantation (SCT), which can be curative in acute and chronic myeloid leukemias, exemplifies the success of immunotherapy for cancer management. However, because of its nonspecific immune response against normal tissue, allo-SCT is associated with high rates of morbidity and mortality, secondary to graft-versus-host disease, which can occur in up to 50% of allo-SCT recipients. Targeted immunotherapy using leukemia vaccines has been heavily investigated, as these vaccines elicit specific immune responses against leukemia cells while sparing normal tissue. Peptide and cellular vaccines have been developed against tumor-specific and leukemia-associated self-antigens. Although not yet considered the standard of care, leukemia vaccines continue to show promising results in the management of the myeloid leukemias.

Alatrash, Gheath; Molldrem, Jeffrey J

2011-01-01

360

Myelopoiesis and Myeloid Leukaemogenesis in the Zebrafish  

PubMed Central

Over the past ten years, studies using the zebrafish model have contributed to our understanding of vertebrate haematopoiesis, myelopoiesis, and myeloid leukaemogenesis. Novel insights into the conservation of haematopoietic lineages and improvements in our capacity to identify, isolate, and culture such haematopoietic cells continue to enhance our ability to use this simple organism to address disease biology. Coupled with the strengths of the zebrafish embryo to dissect developmental myelopoiesis and the continually expanding repertoire of models of myeloid malignancies, this versatile organism has established its niche as a valuable tool to address key questions in the field of myelopoiesis and myeloid leukaemogenesis. In this paper, we address the recent advances and future directions in the field of myelopoiesis and leukaemogenesis using the zebrafish system.

Forrester, A. Michael; Berman, Jason N.; Payne, Elspeth M.

2012-01-01

361

Overexpression of the local bone marrow renin-angiotensin system in acute myeloid leukemia.  

PubMed Central

OBJECTIVES: Local bone marrow renin-angiotensin system (RAS) is an autocrine-paracrine system affecting hematopoiesis. Angiotensin II stimulates the proliferation of bone marrow and umbilical cord blood hematopoietic progenitors. Angiotensin-converting enzyme (ACE) hyperfunction may lead to the acceleration of negative hematopoietic regulator peptide, AcSDKP, metabolism, which in turn lowers its level in the bone marrow microenvironment, finally removing the antiproliferative effect of AcSDKP on the hematopoietic cells and blasts. The aim of this study is therefore to search those major RAS components simultaneously in the leukemic blast cells taken from the bone marrow of patients with acute myeloid leukemia (AML). METHODS: Bone marrow aspiration materials were obtained from 10 patients with AML (8 males, 2 females; median age 48.5 years) and 8 patients with nonmalignant hematological disorders (6 males, 2 females; median age 45 years). EDTA-treated bone marrow samples were stored at -70 degrees C until analysis. Total RNA was extracted from 200-microl bone marrow samples by High Pure RNA Isolation Kit. RESULTS: The medians of expression ratios of AML patient samples have been found 0.736 (IQR 1.359), 0.540 (IQR 0.725), and 0.075 (IQR 0.002) for ACE, ANG and REN genes, respectively. All three gene expressions were found to be significantly higher in the bone marrow samples of AML patients. CONCLUSION: In this study, the expression of the mRNAs of the major RAS components-namely ACE, renin and angiotensinogen-in human bone marrow samples were quantified by reverse transcription-polymerase chain reaction (RT-PCR) to confirm the presence of the local bone marrow RAS. Elucidation of the pathological activity of the local RAS-mediated regulation of the leukemogenesis is both pathobiologically and clinically important, since the angiotensin peptides represent a molecular target in the disease management.

Beyazit, Yavuz; Aksu, Salih; Haznedaroglu, Ibrahim C.; Kekilli, Murat; Misirlioglu, Muge; Tuncer, Serdar; Karakaya, Jale; Koca, Ebru; Buyukasik, Yahya; Sayinalp, Nilgun; Goker, Hakan

2007-01-01

362

Discovery and Characterization of Novel Vascular and Hematopoietic Genes Downstream of Etsrp in Zebrafish  

PubMed Central

The transcription factor Etsrp is required for vasculogenesis and primitive myelopoiesis in zebrafish. When ectopically expressed, etsrp is sufficient to induce the expression of many vascular and myeloid genes in zebrafish. The mammalian homolog of etsrp, ER71/Etv2, is also essential for vascular and hematopoietic development. To identify genes downstream of etsrp, gain-of-function experiments were performed for etsrp in zebrafish embryos followed by transcription profile analysis by microarray. Subsequent in vivo expression studies resulted in the identification of fourteen genes with blood and/or vascular expression, six of these being completely novel. Regulation of these genes by etsrp was confirmed by ectopic induction in etsrp overexpressing embryos and decreased expression in etsrp deficient embryos. Additional functional analysis of two newly discovered genes, hapln1b and sh3gl3, demonstrates their importance in embryonic vascular development. The results described here identify a group of genes downstream of etsrp likely to be critical for vascular and/or myeloid development.

Zhao, Yan; Burgess, Shawn; Lin, Shuo

2009-01-01

363

Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities.  

PubMed Central

PU.1 is a member of the ets family of transcription factors and is expressed exclusively in cells of the hematopoietic lineage. Mice homozygous for a disruption in the PU.1 DNA binding domain are born alive but die of severe septicemia within 48 h. The analysis of these neonates revealed a lack of mature macrophages, neutrophils, B cells and T cells, although erythrocytes and megakaryocytes were present. The absence of lymphoid commitment and development in null mice was not absolute, since mice maintained on antibiotics began to develop normal appearing T cells 3-5 days after birth. In contrast, mature B cells remained undetectable in these older mice. Within the myeloid lineage, despite a lack of macrophages in the older antibiotic-treated animals, a few cells with the characteristics of neutrophils began to appear by day 3. While the PU.1 protein appears not to be essential for myeloid and lymphoid lineage commitment, it is absolutely required for the normal differentiation of B cells and macrophages. Images

McKercher, S R; Torbett, B E; Anderson, K L; Henkel, G W; Vestal, D J; Baribault, H; Klemsz, M; Feeney, A J; Wu, G E; Paige, C J; Maki, R A

1996-01-01

364

Plzf drives MLL-fusion-mediated leukemogenesis specifically in long-term hematopoietic stem cells.  

PubMed

Oncogenic transformation requires unlimited self-renewal. Currently, it remains unclear whether a normal capacity for self-renewal is required for acquiring an aberrant self-renewal capacity. Our results in a new conditional transgenic mouse showed that a mixed lineage leukemia (MLL) fusion oncogene, MLL-ENL, at an endogenous-like expression level led to leukemic transformation selectively in a restricted subpopulation of hematopoietic stem cells (HSCs) through upregulation of promyelocytic leukemia zinc finger (Plzf). Interestingly, forced expression of Plzf itself immortalized HSCs and myeloid progenitors in vitro without upregulation of Hoxa9/Meis1, which are well-known targets of MLL fusion proteins, whereas its mutant lacking the BTB/POZ domain did not. In contrast, depletion of Plzf suppressed the MLL-fusion-induced leukemic transformation of HSCs in vitro and in vivo. Gene expression analyses of human clinical samples showed that a subtype of PLZF-high MLL-rearranged myeloid leukemia cells was closely associated with the gene expression signature of HSCs. These findings suggested that MLL fusion protein enhances the self-renewal potential of normal HSCs to develop leukemia, in part through a Plzf-driven self-renewal program. PMID:23838347

Ono, Ryoichi; Masuya, Masahiro; Nakajima, Hideaki; Enomoto, Yutaka; Miyata, Eri; Nakamura, Akihide; Ishii, Satomi; Suzuki, Kei; Shibata-Minoshima, Fumi; Katayama, Naoyuki; Kitamura, Toshio; Nosaka, Tetsuya

2013-07-09

365

The Oncogenic TLS-ERG Fusion Protein Exerts Different Effects in Hematopoietic Cells and Fibroblasts  

PubMed Central

The oncogenic TLS-ERG fusion protein is found in human myeloid leukemia and Ewing's sarcoma as a result of specific chromosomal translocation. To unveil the potential mechanism(s) underlying cellular transformation, we have investigated the effects of TLS-ERG on both gene transcription and RNA splicing. Here we show that the TLS protein forms complexes with RNA polymerase II (Pol II) and the serine-arginine family of splicing factors in vivo. Deletion analysis of TLS-ERG in both mouse L-G myeloid progenitor cells and NIH 3T3 fibroblasts revealed that the RNA Pol II-interacting domain of TLS-ERG resides within the first 173 amino acids. While TLS-ERG repressed expression of the luciferase reporter gene driven by glycoprotein IX promoter in L-G cells but not in NIH 3T3 cells, the fusion protein was able to affect splicing of the E1A reporter in NIH 3T3 cells but not in L-G cells. To identify potential target genes of TLS-ERG, the fusion protein and its mutants were stably expressed in both L-G and NIH 3T3 cells through retroviral transduction. Microarray analysis of RNA samples from these cells showed that TLS-ERG activates two different sets of genes sharing little similarity in the two cell lines. Taken together, these results suggest that the oncogenic TLS-ERG fusion protein transforms hematopoietic cells and fibroblasts via different pathways.

Zou, Junhui; Ichikawa, Hitoshi; Blackburn, Michael L.; Hu, Hsien-Ming; Zielinska-Kwiatkowska, Anna; Mei, Qi; Roth, Gerald J.; Chansky, Howard A.; Yang, Liu

2005-01-01

366

Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development  

PubMed Central

Hematopoietic stem cells (HSC) are responsible for the life-long production of the blood system and are pivotal cells in hematologic transplantation therapies. During mouse and human development, the first HSCs are produced in the aorta-gonad-mesonephros region. Subsequent to this emergence, HSCs are found in other anatomical sites of the mouse conceptus. While the mouse placenta contains abundant HSCs at midgestation, little is known concerning whether HSCs or hematopoietic progenitors are present and supported in the human placenta during development. In this study we show, over a range of developmental times including term, that the human placenta contains hematopoietic progenitors and HSCs. Moreover, stromal cell lines generated from human placenta at several developmental time points are pericyte-like cells and support human hematopoiesis. Immunostaining of placenta sections during development localizes hematopoietic cells in close contact with pericytes/perivascular cells. Thus, the human placenta is a potent hematopoietic niche throughout development.

Robin, Catherine; Bollerot, Karine; Mendes, Sandra; Haak, Esther; Crisan, Mihaela; Cerisoli, Francesco; Lauw, Ivoune; Kaimakis, Polynikis; Jorna, Ruud; Vermeulen, Mark; Kayser, Manfred; van der Linden, Reinier; Imanirad, Parisa; Verstegen, Monique; Nawaz-Yousaf, Humaira; Papazian, Natalie; Steegers, Eric; Cupedo, Tom; Dzierzak, Elaine

2009-01-01

367

FAM20: an evolutionarily conserved family of secreted proteins expressed in hematopoietic cells  

PubMed Central

Background Hematopoiesis is a complex developmental process controlled by a large number of factors that regulate stem cell renewal, lineage commitment and differentiation. Secreted proteins, including the hematopoietic growth factors, play critical roles in these processes and have important biological and clinical significance. We have employed representational difference analysis to identify genes that are differentially expressed during experimentally induced myeloid differentiation in the murine EML hematopoietic stem cell line. Results One identified clone encoded a previously unidentified protein of 541 amino acids that contains an amino terminal signal sequence but no other characterized domains. This protein is a member of family of related proteins that has been named family with sequence similarity 20 (FAM20) with three members (FAM20A, FAM20B and FAM20C) in mammals. Evolutionary comparisons revealed the existence of a single FAM20 gene in the simple vertebrate Ciona intestinalis and the invertebrate worm Caenorhabditis elegans and two genes in two insect species, Drosophila melanogaster and Anopheles gambiae. Six FAM20 family members were identified in the genome of the pufferfish, Fugu rubripes and five members in the zebrafish, Danio rerio. The mouse Fam20a protein was ectopically expressed in a mammalian cell line and found to be a bona fide secreted protein and efficient secretion was dependent on the integrity of the signal sequence. Expression analysis revealed that the Fam20a gene was indeed differentially expressed during hematopoietic differentiation and that the other two family members (Fam20b and Fam20c) were also expressed during hematcpoiesis but that their mRNA levels did not vary significantly. Likewise FAM20A was expressed in more limited set of human tissues than the other two family members. Conclusions The FAM20 family represents a new family of secreted proteins with potential functions in regulating differentiation and function of hematopoietic and other tissues. The Fam20a mRNA was only expressed during early stages of hematopoietic development and may play a role in lineage commitment or proliferation. The expansion in gene number in different species suggests that the family has evolved as a result of several gene duplication events that have occurred in both vertebrates and invertebrates.

Nalbant, Demet; Youn, Hyewon; Nalbant, S Isil; Sharma, Savitha; Cobos, Everardo; Beale, Elmus G; Du, Yang; Williams, Simon C

2005-01-01

368

Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia  

ClinicalTrials.gov

Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

2013-05-07

369

Daunorubicin Hydrochloride, Cytarabine and Oblimersen Sodium in Treating Patients With Previously Untreated Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2013-06-04

370

Pathogenesis of plexiform neurofibroma: tumor-stromal/hematopoietic interactions in tumor progression.  

PubMed

Neurofibromatosis type 1 (NF1) is a genetic disease that results from either heritable or spontaneous autosomal dominant mutations in the NF1 gene. A second-hit mutation precedes the predominant NF1 neoplasms, which include myeloid leukemia, optic glioma, and plexiform neurofibroma. Despite this requisite NF1 loss of heterozygosity in the tumor cell of origin, nontumorigenic cells contribute to both generalized and specific disease manifestations. In mouse models of plexiform neurofibroma formation, Nf1 haploinsufficient mast cells promote inflammation, accelerating tumor formation and growth. These recruited mast cells, hematopoietic effector cells long known to permeate neurofibroma tissue, mediate key mitogenic signals that contribute to vascular ingrowth, collagen deposition, and tumor growth. Thus, the plexiform neurofibroma microenvironment involves a tumor/stromal interaction with the hematopoietic system that depends, at the molecular level, on a stem cell factor/c-kit-mediated signaling axis. These observations parallel findings in other NF1 disease manifestations and are clearly relevant to medical management of these neurofibromas. PMID:22077553

Staser, Karl; Yang, Feng-Chun; Clapp, D Wade

2011-11-07

371

Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain.  

PubMed

Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain. PMID:19525966

Schweizerhof, Matthias; Stösser, Sebastian; Kurejova, Martina; Njoo, Christian; Gangadharan, Vijayan; Agarwal, Nitin; Schmelz, Martin; Bali, Kiran Kumar; Michalski, Christoph W; Brugger, Stefan; Dickenson, Anthony; Simone, Donald A; Kuner, Rohini

2009-06-07

372

Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1.  

PubMed

The Fanconi anemia group C protein (FANCC) plays an important role in hematopoiesis by ensuring the survival of hematopoietic progenitor cells through an unknown mechanism. We investigated the function of FANCC by identifying FANCC-binding proteins in hematopoietic cells. Here we show that glutathione S-transferase P1-1 (GSTP1) interacts with FANCC, and that overexpression of both proteins in a myeloid progenitor cell line prevents apoptosis following factor deprivation. FANCC increases GSTP1 activity after the induction of apoptosis. GSTP1 is an enzyme that catalyzes the detoxification of xenobiotics and by-products of oxidative stress, and it is frequently upregulated in neoplastic cells. Although FANCC lacks homology with conventional disulfide reductases, it functions by preventing the formation of inactivating disulfide bonds within GSTP1 during apoptosis. The prevention of protein oxidation by FANCC reveals a novel mechanism of enzyme regulation during apoptosis and has implications for the treatment of degenerative diseases with thiol reducing agents. PMID:11433346

Cumming, R C; Lightfoot, J; Beard, K; Youssoufian, H; O'Brien, P J; Buchwald, M

2001-07-01

373

SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors.  

PubMed

Hematopoietic stem cells (HSCs) and multipotent hematopoietic progenitors (MPPs) are routinely isolated using various markers but remain heterogeneous. Here we show that four SLAM family markers, CD150, CD48, CD229, and CD244, can distinguish HSCs and MPPs from restricted progenitors and subdivide them into a hierarchy of functionally distinct subpopulations with stepwise changes in cell-cycle status, self-renewal, and reconstituting potential. CD229 expression largely distinguished lymphoid-biased HSCs from rarely dividing myeloid-biased HSCs, enabling prospective enrichment of these HSC subsets. Differences in CD229 and CD244 expression resolved CD150(-)CD48(-/low)Lineage(-/low)Sca-1(+)c-Kit(+) cells into a hierarchy of highly purified MPPs that retained erythroid and platelet potential but exhibited progressive changes in mitotic activity and reconstituting potential. Use of these markers, and reconstitution assays, showed that conditional deletion of Scf from endothelial cells and perivascular stromal cells eliminated the vast majority of bone marrow HSCs, including nearly all CD229(-/low) HSCs, demonstrating that quiescent HSCs are maintained by a perivascular niche. PMID:23827712

Oguro, Hideyuki; Ding, Lei; Morrison, Sean J

2013-07-01

374

Incomplete Splicing, Cell Division Defects and Hematopoietic Blockage in dhx8 Mutant Zebrafish  

PubMed Central

Vertebrate hematopoiesis is a complex developmental process that is controlled by genes in diverse pathways. To identify novel genes involved in early hematopoiesis, we conducted an ENU (N-ethyl-N-nitrosourea) mutagenesis screen in zebrafish. The mummy (mmy) line was investigated because of its multiple hematopoietic defects. Homozygous mmy embryos lacked circulating blood cells types and were dead by 30 hours post-fertilization (hpf). The mmy mutants did not express myeloid markers and had significantly decreased expression of progenitor and erythroid markers in primitive hematopoiesis. Through positional cloning, we identified a truncation mutation in dhx8 in the mmy fish. dhx8 is the zebrafish ortholog of the yeast splicing factor prp22, which is a DEAH-box RNA helicase. Mmy mutants had splicing defects in many genes, including several hematopoietic genes. Mmy embryos also showed cell division defects as characterized by disorganized mitotic spindles and formation of multiple spindle poles in mitotic cells. These cell division defects were confirmed by DHX8 knockdown in HeLa cells. Together, our results confirm that dhx8 is involved in mRNA splicing and suggest that it is also important for cell division during mitosis. This is the first vertebrate model for dhx8, whose function is essential for primitive hematopoiesis in developing embryos.

English, Milton A.; Lei, Lin; Blake, Trevor; Wincovitch, Stephen M.; Sood, Raman; Azuma, Mizuki; Hickstein, Dennis; Liu, P. Paul

2012-01-01

375

The combination of valproic acid and lithium delays hematopoietic stem/progenitor cell differentiation.  

PubMed

Despite increasing knowledge on the regulation of hematopoietic stem/progenitor cell (HSPC) self-renewal and differentiation, in vitro control of stem cell fate decisions has been difficult. The ability to inhibit HSPC commitment in culture may be of benefit to cell therapy protocols. Small molecules can serve as tools to manipulate cell fate decisions. Here, we tested 2 small molecules, valproic acid (VPA) and lithium (Li), to inhibit differentiation. HSPCs exposed to VPA and Li during differentiation-inducing culture preserved an immature cell phenotype, provided radioprotection to lethally irradiated recipients, and enhanced in vivo repopulating potential. Anti-differentiation effects of VPA and Li were observed also at the level of committed progenitors, where VPA re-activated replating activity of common myeloid progenitor and granulocyte macrophage progenitor cells. Furthermore, VPA and Li synergistically preserved expression of stem cell-related genes and repressed genes involved in differentiation. Target genes were collectively co-regulated during normal hematopoietic differentiation. In addition, transcription factor networks were identified as possible primary regulators. Our results show that the combination of VPA and Li potently delays differentiation at the biologic and molecular levels and provide evidence to suggest that combinatorial screening of chemical compounds may uncover possible additive/synergistic effects to modulate stem cell fate decisions. PMID:22327222

Walasek, Marta A; Bystrykh, Leonid; van den Boom, Vincent; Olthof, Sandra; Ausema, Albertina; Ritsema, Martha; Huls, Gerwin; de Haan, Gerald; van Os, Ronald

2012-02-10

376

Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome  

PubMed Central

Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/’fatigue’ of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/’fatigue’ of 50 or over, are likely to have poor outcomes.

Deschler, Barbara; Ihorst, Gabriele; Platzbecker, Uwe; Germing, Ulrich; Marz, Eva; de Figuerido, Marcelo; Fritzsche, Kurt; Haas, Peter; Salih, Helmut R.; Giagounidis, Aristoteles; Selleslag, Dominik; Labar, Boris; de Witte, Theo; Wijermans, Pierre; Lubbert, Michael

2013-01-01

377

Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes.  

PubMed

Polycomb-group (PcG) proteins form the multiprotein polycomb repressive complexes (PRC) 1 and 2, and function as transcriptional repressors through histone modifications. They maintain the proliferative capacity of hematopoietic stem and progenitor cells by repressing the transcription of tumor suppressor genes, namely Ink4a and Arf, and thus have been characterized as oncogenes. However, the identification of inactivating mutations in the PcG gene, EZH2, unveiled a tumor suppressor function in myeloid malignancies, including primary myelofibrosis (PMF). Here, we show that loss of another PcG gene, Bmi1, causes pathological hematopoiesis similar to PMF. In a mouse model, loss of Bmi1 in Ink4a-Arf(-/-) hematopoietic cells induced abnormal megakaryocytopoiesis accompanied by marked extramedullary hematopoiesis, which eventually resulted in lethal myelofibrosis. Absence of Bmi1 caused derepression of a cohort of genes, including Hmga2, which is an oncogene overexpressed in PMF. Chromatin immunoprecipitation assays revealed that Bmi1 directly represses the transcription of Hmga2. Overexpression of Hmga2 in hematopoietic stem cells induced a myeloproliferative state with enhanced megakaryocytopoiesis in mice, implicating Hmga2 in the development of pathological hematopoiesis in the absence of Bmi1. Our findings provide the first genetic evidence of a tumor suppressor function of Bmi1 and uncover the role of PcG proteins in restricting growth by silencing oncogenes. PMID:22351929

Oguro, Hideyuki; Yuan, Jin; Tanaka, Satomi; Miyagi, Satoru; Mochizuki-Kashio, Makiko; Ichikawa, Hitoshi; Yamazaki, Satoshi; Koseki, Haruhiko; Nakauchi, Hiromitsu; Iwama, Atsushi

2012-02-20

378

Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes  

PubMed Central

Polycomb-group (PcG) proteins form the multiprotein polycomb repressive complexes (PRC) 1 and 2, and function as transcriptional repressors through histone modifications. They maintain the proliferative capacity of hematopoietic stem and progenitor cells by repressing the transcription of tumor suppressor genes, namely Ink4a and Arf, and thus have been characterized as oncogenes. However, the identification of inactivating mutations in the PcG gene, EZH2, unveiled a tumor suppressor function in myeloid malignancies, including primary myelofibrosis (PMF). Here, we show that loss of another PcG gene, Bmi1, causes pathological hematopoiesis similar to PMF. In a mouse model, loss of Bmi1 in Ink4a-Arf?/? hematopoietic cells induced abnormal megakaryocytopoiesis accompanied by marked extramedullary hematopoiesis, which eventually resulted in lethal myelofibrosis. Absence of Bmi1 caused derepression of a cohort of genes, including Hmga2, which is an oncogene overexpressed in PMF. Chromatin immunoprecipitation assays revealed that Bmi1 directly represses the transcription of Hmga2. Overexpression of Hmga2 in hematopoietic stem cells induced a myeloproliferative state with enhanced megakaryocytopoiesis in mice, implicating Hmga2 in the development of pathological hematopoiesis in the absence of Bmi1. Our findings provide the first genetic evidence of a tumor suppressor function of Bmi1 and uncover the role of PcG proteins in restricting growth by silencing oncogenes.

Oguro, Hideyuki; Yuan, Jin; Tanaka, Satomi; Miyagi, Satoru; Mochizuki-Kashio, Makiko; Ichikawa, Hitoshi; Yamazaki, Satoshi; Koseki, Haruhiko; Nakauchi, Hiromitsu

2012-01-01

379

T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures.  

PubMed

The efficient generation of hematopoietic stem cells from human pluripotent stem cells is dependent on the appropriate specification of the definitive hematopoietic program during differentiation. In this study, we used T lymphocyte potential to track the onset of definitive hematopoiesis from human embryonic and induced pluripotent stem cells differentiated with specific morphogens in serum- and stromal-free cultures. We show that this program develops from a progenitor population with characteristics of hemogenic endothelium, including the expression of CD34, VE-cadherin, GATA2, LMO2, and RUNX1. Along with T cells, these progenitors display the capacity to generate myeloid and erythroid cells. Manipulation of Activin/Nodal signaling during early stages of differentiation revealed that development of the definitive hematopoietic progenitor population is not dependent on this pathway, distinguishing it from primitive hematopoiesis. Collectively, these findings demonstrate that it is possible to generate T lymphoid progenitors from pluripotent stem cells and that this lineage develops from a population whose emergence marks the onset of human definitive hematopoiesis. PMID:23219550

Kennedy, Marion; Awong, Geneve; Sturgeon, Christopher M; Ditadi, Andrea; LaMotte-Mohs, Ross; Zúñiga-Pflücker, Juan Carlos; Keller, Gordon

2012-12-07

380

CD4+CD56+CD68+hematopoietic tumor of probable plasmacytoid monocyte derivation with weak expression of cytoplasmic CD3.  

PubMed

Hematopoietic neoplasm coexpressing CD4 and CD56 includes a subset of acute myeloid leukemia with myelomonocytic differentiation, plasmacytoid monocyte tumor, and other immature hematopoietic neoplasms of undefined origin. Herein, we report a CD4+CD56+CD68+ hematopoietic tumor that was thought to be a tumor of plasmacytoid monocytes. This case is unique in the absence of accompanying myelomonocytic leukemia and the faint expression of cCD3 on the tumor cells. The patient was a 22-yr old man presented with multiple lymphadenopathy and an involvement of the bone marrow. Tumor cells were large and monomorphic with an angulated eosinophilic cytoplasm of moderate amount. Nuclei of most tumor cells were eccentric and round with one or two prominent nucleoli. Rough endoplasmic reticulum was prominent in electron microscopic examination. Tumor cells expressed CD4, CD7, CD10, CD45RB, CD56, CD68, and HLA-DR and were negative for CD1a, CD2, sCD3, CD5, CD13, CD14, CD20, CD33, CD34, CD43, CD45RA, TIA-1, S-100, and TdT. cCD3 was not detected in the immunostaining using paraffin tissue, but was faintly expressed in flow cytometry and immunostaining using a touch imprint slide. T-cell receptor gene rearrangement analysis and EBV in situ hybridization showed negative results. Cytochemically, myeloperoxidase, Sudan black B, and alpha naphthyl butyrate esterase were all negative. PMID:12483012

Ko, Young Hyeh; Kim, Sun Hee; Park, Keunchil; Ree, Howe Jung

2002-12-01

381

Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells  

PubMed Central

Activating mutations in protein tyrosine phosphatase 11 (Ptpn11) have been identified in childhood acute leukemias, in addition to juvenile myelomonocytic leukemia (JMML), which is a myeloproliferative disorder (MPD). It is not clear whether activating mutations of this phosphatase play a causal role in the pathogenesis of acute leukemias. If so, the cell origin of leukemia-initiating stem cells (LSCs) remains to be determined. Ptpn11E76K mutation is the most common and most active Ptpn11 mutation found in JMML and acute leukemias. However, the pathogenic effects of this mutation have not been well characterized. We have created Ptpn11E76K conditional knock-in mice. Global Ptpn11E76K/+ mutation results in early embryonic lethality. Induced knock-in of this mutation in pan hematopoietic cells leads to MPD as a result of aberrant activation of hematopoietic stem cells (HSCs) and myeloid progenitors. These animals subsequently progress to acute leukemias. Intriguingly, in addition to acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia/lymphoma (T-ALL) and B-ALL are evolved. Moreover, tissue-specific knock-in of Ptpn11E76K/+ mutation in lineage-committed myeloid, T lymphoid, and B lymphoid progenitors also results in AML, T-ALL, and B-ALL, respectively. Further analyses have revealed that Shp2 (encoded by Ptpn11) is distributed to centrosomes and that Ptpn11E76K/+ mutation promotes LSC development, partly by causing centrosome amplification and genomic instability. Thus, Ptpn11E76K mutation has non–lineage-specific effects on malignant transformation of hematopoietic cells and initiates acute leukemias at various stages of hematopoiesis.

Xu, Dan; Liu, Xia; Yu, Wen-Mei; Meyerson, Howard J.; Guo, Caiying; Gerson, Stanton L.

2011-01-01

382

Lethal proliferation of erythroid precursors in a neonate with a germline PTPN11 mutation  

Microsoft Academic Search

We report a neonate with hypertrophic cardiomyopathy and lethal myeloproliferative disorder with excessively proliferating\\u000a immature erythroid precursors infiltrating non-hematopoietic organs. Mutational analysis uncovered a germline mutation in\\u000a the Noonan syndrome\\/LEOPARD syndrome (NS\\/LS) gene PTPN11. In conclusion, this case report suggests that congenital myeloproliferative disorders in association with germline PTPN11 mutations may affect the erythroid lineage.

Christian Peter Kratz; Michaela Nathrath; Peter Freisinger; Petra Dressel; Hans-Peter Assmuss; Cornelia Klein; Ayami Yoshimi; Stefan Burdach; Charlotte Marie Niemeyer

2006-01-01

383

Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors.  

PubMed

TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA and is frequently mutated in myeloid malignancies, including myeloproliferative neoplasms. Here we show that the level of 5-hmC is decreased in granulocyte DNA from myeloproliferative neoplasm patients with TET2 mutations compared with granulocyte DNA from healthy patients. Inhibition of TET2 by RNA interference decreases 5-hmC levels in both human leukemia cell lines and cord blood CD34(+) cells. These results confirm the enzymatic function of TET2 in human hematopoietic cells. Knockdown of TET2 in cord blood CD34(+) cells skews progenitor differentiation toward the granulomonocytic lineage at the expense of lymphoid and erythroid lineages. In addition, by monitoring in vitro granulomonocytic development we found a decreased granulocytic differentiation and an increase in monocytic cells. Our results indicate that TET2 disruption affects 5-hmC levels in human myeloid cells and participates in the pathogenesis of myeloid malignancies through the disturbance of myeloid differentiation. PMID:21734233

Pronier, Elodie; Almire, Carole; Mokrani, Hayat; Vasanthakumar, Aparna; Simon, Audrey; da Costa Reis Monte Mor, Barbara; Massé, Aline; Le Couédic, Jean-Pierre; Pendino, Frédéric; Carbonne, Bruno; Larghero, Jérôme; Ravanat, Jean-Luc; Casadevall, Nicole; Bernard, Olivier A; Droin, Nathalie; Solary, Eric; Godley, Lucy A; Vainchenker, William; Plo, Isabelle; Delhommeau, François

2011-07-06

384

Allogeneic transplantation as post-remission therapy for cytogenetically high-risk acute myeloid leukemia: landmark analysis from a single prospective multicenter trial  

PubMed Central

Background Allogeneic hematopoietic cell transplantation is considered the preferred post-remission therapy in patients with acute myeloid leukemia cytogenetically defined as being at high risk. To substantiate evidence for allogeneic hematopoietic cell transplantation in first complete remission in these high-risk patients we performed a landmark analysis within a single prospective multicenter treatment trial. Design and Methods By the time of analysis, 2,347 patients had been accrued into the AMLCG 99 trial between 1999 – 2007. Out of this population, 243 patients under 60 years old fulfilled the criteria for high-risk cytogenetics. Landmark analyses were performed with a control cohort, who remained in first complete remission at least the median time from complete remission to transplantation in the intervention group. Results After standardized induction therapy, 111 patients under 60 years old achieved complete remission. A matched allogeneic donor was identified for 59 patients (30 sibling donors, 29 unrelated donors). Fifty-five patients received an allogeneic hematopoietic cell transplant after a median time of 88 days in first complete remission. Of the remaining 56 patients, 21 relapsed within 90 days after achieving first complete remission and for 7 patients with relevant comorbidities no donors search was initiated, leaving 28 patients given conventional post-remission therapy as the control cohort. The median follow-up of surviving patients was 60.4 months. Patients with an allogeneic donor had substantially better 5-year overall and relapse-free survival rates than the control group (48% versus 18%, P=0.004 and 39% versus 10%, P<0.001, respectively). A survival benefit from transplantation was evident regardless of donor type, age and monosomal karyotype. Conclusions Beyond evidence available for subgroups of high-risk patients, the findings of this study establish in a broader manner that allogeneic hematopoietic cell transplantation is a preferable consolidation treatment for patients with acute myeloid leukemia and high-risk cytogenetics. The study was registered at Clinicaltrials.gov as NCT00266136.

Stelljes, Matthias; Beelen, Dietrich W.; Braess, Jan; Sauerland, Maria C.; Heinecke, Achim; Berning, Bjorna; Kolb, Hans J.; Holler, Ernst; Schwerdtfeger, Rainer; Arnold, Renate; Spiekermann, Karsten; Muller-Tidow, Carsten; Serve, Hubert L.; Silling, Gerda; Hiddemann, Wolfgang; Berdel, Wolfgang E.; Buchner, Thomas; Kienast, Joachim

2011-01-01

385

Ionizing radiation and hematopoietic malignancies  

PubMed Central

Somatic evolution, which underlies tumor progression, is driven by two essential components: (1) diversification of phenotypes through heritable mutations and epigenetic changes and (2) selection for mutant clones which possess higher fitness. Exposure to ionizing radiation (IR) is highly associated with increased risk of carcinogenesis. This link is traditionally attributed to causation of oncogenic mutations through the mutagenic effects of irradiation. On the other hand, potential effects of irradiation on altering fitness and increasing selection for mutant clones are frequently ignored. Recent studies bring the effects of irradiation on fitness and selection into focus, demonstrating that IR exposure results in stable reductions in the fitness of hematopoietic stem and progenitor cell populations. These reductions of fitness are associated with alteration of the adaptive landscape, increasing the selective advantages conferred by certain oncogenic mutations. Therefore, the link between irradiation and carcinogenesis might be more complex than traditionally appreciated: while mutagenic effects of irradiation should increase the probability of occurrence of oncogenic mutations, IR can also work as a tumor promoter, increasing the selective expansion of clones bearing mutations which become advantageous in the irradiation-altered environment, such as activated mutations in Notch1 or disrupting mutations in p53.

Fleenor, Courtney J; Marusyk, Andriy

2010-01-01

386

Lenalidomide in Treating Older Patients With Acute Myeloid Leukemia  

ClinicalTrials.gov

Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

2013-07-02

387

Bone marrow necrosis complicating chronic myeloid leukaemia.  

PubMed

Two women with chronic myeloid leukaemia in chronic phase were found to have bone marrow necrosis when severe bone pains and falling blood counts prompted a marrow examination to exclude blast transformation. One patient survived for 12 months following the event without transforming. The second patient died soon after and was found to have widespread extramedullary disease. PMID:1934927

Macheta, A T; Cinkotai, K I; Love, E M; Geary, C G; Liu Yin, J A

1991-01-