Increased cell apoptosis in bone marrow trephine biopsies and immunomagnetically isolated myeloid progenitor cells in patients with chronic idiopathic neutropenia

To probe the pathophysiologic mechanisms underlying neutropenia in patients with chronic idiopathic neutropenia (CIN) with hypoplastic and left-shifted granulocytic series in the bone marrow (BM), we have studied granulocytopoiesis in 32 adults with CIN by evaluating the number and survival characteristics of cells in several stages of granulocyte differentiation using flow cytometry and BM culture assays. We found that patients with CIN displayed a low percentage of CD34+/CD33+ cells, defective granulocyte colony-forming unit (CFU-G) growth potential of BM mononuclear or purified CD34+ cells, and low CFU-G recovery in long-term BM cultures (LTBMCs), compared with controls (n = 46). A low percentage of CD34+/CD33+ cells in patients was associated with accelerated apoptosis and Fas overexpression within this cell compartment compared with controls. No significant difference was documented in the percentage of apoptotic cells or the Fas+ cells within the fractionated CD34+/CD33−, CD34−/CD33+, and CD34−/CD33−/CD15+ BM subpopulations or the peripheral blood neutrophils, suggesting that the underlying cellular defect in CIN probably concerns the committed granulocyte progenitors. LTBMC stromal layers from patients produced abnormally high amounts of tumor necrosis factor α and cytokine levels in culture supernatants inversely correlated with the number of myeloid progenitor cells and positively with the proportion of apoptotic CD34+ cells. Patient LTBMC stromal layers displayed pathologic interferon γ and Fas-ligand mRNA expression and failed to support normal myelopoiesis. These data suggest that impaired granulocytopoiesis in CIN is probably due to overproduction of inflammatory cytokines by immune cells within the BM microenvironment that may exert an inhibitory effect on myelopoiesis by inducing Fas-mediated apoptosis in the granulocyte progenitors.

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Low frequency of myeloid progenitor cells in chronic idiopathic neutropenia of adults may be related to increased production of TGF-β1 by bone marrow stromal cells

European Journal Of Haematology ◽

10.1111/j.1600-0609.1999.tb01763.x ◽

2009 ◽

Vol 63 (3) ◽

pp. 154-162 ◽

Cited By ~ 28

Author(s):

Helen A. Papadaki ◽

Kalliopi Giouremou ◽

George D. Eliopoulos

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Low Frequency ◽

Marrow Stromal Cells ◽

Myeloid Progenitor ◽

Chronic Idiopathic Neutropenia ◽

Myeloid Progenitor Cells ◽

Tgf Β1

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Bone marrow lymphoid and myeloid progenitor cells are suppressed in 7,12-dimethylbenz(a)anthracene (DMBA) treated mice

Toxicology ◽

10.1016/j.tox.2010.02.009 ◽

2010 ◽

Vol 271 (1-2) ◽

pp. 27-35 ◽

Cited By ~ 11

Author(s):

A.U. N’jai ◽

M. Larsen ◽

L. Shi ◽

C.R. Jefcoate ◽

C.J. Czuprynski

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

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Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia

Blood ◽

10.1182/blood.v79.9.2229.2229 ◽

1992 ◽

Vol 79 (9) ◽

pp. 2229-2236 ◽

Cited By ~ 69

Author(s):

MJ Robertson ◽

RJ Soiffer ◽

AS Freedman ◽

SL Rabinowe ◽

KC Anderson ◽

...

Keyword(s):

Monoclonal Antibody ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Progenitor Cells ◽

Myeloid Leukemia ◽

Red Blood Cell Transfusion ◽

Hematopoietic Stem ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells ◽

Acute Myeloid

Abstract The CD33 antigen, identified by murine monoclonal antibody anti-MY9, is expressed by clonogenic leukemic cells from almost all patients with acute myeloid leukemia; it is also expressed by normal myeloid progenitor cells. Twelve consecutive patients with de novo acute myeloid leukemia received myeloablative therapy followed by infusion of autologous marrow previously treated in vitro with anti-MY9 and complement. Anti-MY9 and complement treatment eliminated virtually all committed myeloid progenitors (colony-forming unit granulocyte- macrophage) from the autografts. Nevertheless, in the absence of early relapse of leukemia, all patients showed durable trilineage engraftment. The median interval post bone marrow transplantation (BMT) required to achieve an absolute neutrophil count greater than 500/microL was 43 days (range, 16 to 75), to achieve a platelet count greater than 20,000/microL without transfusion was 92 days (range, 35 to 679), and to achieve red blood cell transfusion independence was 105 days (range, 37 to 670). At the time of BM harvest, 10 patients were in second remission, one patient was in first remission, and one patient was in third remission. Eight patients relapsed 3 to 18 months after BMT. Four patients transplanted in second remission remain disease-free 34+, 37+, 52+, and 57+ months after BMT. There was no treatment-related mortality. Early engraftment was significantly delayed in patients receiving CD33-purged autografts compared with concurrently treated patients receiving CD9/CD10-purged autografts for acute lymphoblastic leukemia or patients receiving CD6-purged allografts from HLA- compatible sibling donors. In contrast, both groups of autograft patients required a significantly longer time to achieve neutrophil counts greater than 500/microL and greater than 1,000/microL than did patients receiving normal allogeneic marrow. CD33(+)-committed myeloid progenitor cells thus appear to play an important role in the early phase of hematopoietic reconstitution after BMT. However, our results also show that human marrow depleted of CD33+ cells can sustain durable engraftment after myeloablative therapy, and provide further evidence that the CD33 antigen is absent from the human pluripotent hematopoietic stem cell.

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Diversity and Molecular Modeling of Neutrophil Elastase Mutations in Patients with Severe Congenital Neutropenia and Acute Myelogenous Leukemia.

Blood ◽

10.1182/blood.v104.11.1454.1454 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1454-1454

Author(s):

Andrew A.G. Aprikyan ◽

Steve Stein ◽

Nara A. Markosyan ◽

Maxim Totrov ◽

Ruben Abagyan ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Neutrophil Elastase ◽

Apoptotic Cell ◽

Myelogenous Leukemia ◽

Congenital Neutropenia ◽

Deletion Mutations ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells ◽

Acute Myelogenous

Abstract Severe congenital neutropenia (SCN) is an inheritable hematopoietic disorder that is characterized by extremely low levels of neutrophils in peripheral circulation and maturation arrest of bone marrow myeloid progenitor cells at the promyelocytic stage of differentiation. SCN patients have recurring severe infections and approximately 10% of these patients evolve to develop acute myelogenous leukemia. Recently we reported that an impaired cell survival and cell cycle arrest of bone marrow myeloid progenitor cells was observed in SCN patients compared with controls. We also reported various heterozygous mutations in the neutrophil elastase (NE) gene encoding a serine protease in approximately 80% of SCN patients. We hypothesized that mutations in the NE gene trigger apoptotic cell death of myeloid progenitor cells and subsequent severe neutropenia. Mutational analysis of 15 families with one or more affected family members revealed that mutant NE was present only in affected but not in healthy members of these families suggesting the causative role for mutant NE in pathogenesis of SCN. Sequencing analysis revealed that none of SCN patients negative for NE mutations examined had mutations in the Gfi-1 or WAS gene. Sequencing DNA samples of SCN and SCN/AML patients revealed 40 mutations that are distributed primarily throughout the exons 2 through 5 of the NE gene and result in substitution, deletion, insertion, or truncation mutations. Molecular modeling of the tertiary structure of NE revealed that all these mutations can be grouped into three major categories. The first category includes 19 substitution and insertion mutations that are grouped around the N-glycosylation sites of the neutrophil elastase and may lead to abnormal targeting and subcellular localization of the mutant protease. The second group includes 9 substitution and deletion mutations that alter the side loop of the NE that is necessary for proper oligomerization of neutrophil elastase. The third category includes 12 substitution, truncation, and deletion mutations that either alter or completely eliminate the carboxy-terminus of the mutant protein leading to conformational changes of the binding pocket of the NE, and subsequently to altered substrate specificity and/or an acquired resistance to elastase inhibitors. SCN patients that evolved to develop AML had either substitution, deletion, or truncation mutations from each of the three categories described above. Most mutations are clearly non-conservative, have destabilizing effect on oligomeric structure of mutant protein, and alter dramatically the affinity of mutant NE to various factors participating in its processing and intracellular transport. Flow cytometry analysis of annexin V-labeled cells revealed that expression of representative mutant but not normal NE from each of the three categories of NE mutations in human promyelocytic HL-60 cells triggered apoptotic cell death similar to that observed in bone marrow progenitor cells in SCN patients. These data indicate that impaired cell survival and block of differentiation in SCN is due to heterozygous mutations in the neutrophil elastase gene. Current studies focused on design and screen of specific protease inhibitors capable of blocking the pro-apoptotic effect of mutant neutrophil elastase.

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Peripheral Blood Cytogenetic Studies in Hematological Neoplasms: Predictors of Obtaining Metaphases for Analysis.

Blood ◽

10.1182/blood.v110.11.3504.3504 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3504-3504

Author(s):

Kebede Hussein ◽

Rhett P. Ketterling ◽

Gordon W. Dewald ◽

Rachael L. Hulshizer ◽

Daniel G. Kuffel ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Clinical Diagnosis ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Cytogenetic Study ◽

Lymphocytic Leukemia ◽

Myeloid Progenitor ◽

Cytogenetic Studies ◽

Myeloid Progenitor Cells

Abstract Background: Peripheral blood (PB) is sometimes used in place of bone marrow (BM) for cytogenetic studies during the evaluation of hematologic malignancies. We looked for clinical or laboratory features that predict success in obtaining analyzable metaphases during PB chromosome studies. Methods: The Mayo Clinic cytogenetics database was queried to identify adult cases (age > 18 years) with suspected or established hematologic neoplasm in whom PB cytogenetic studies were performed. Success defined as the acquisition of at least two metaphases, was correlated with clinical and laboratory information corresponding to the time of the PB cytogenetic study. Results: A total of 242 PB cytogenetic studies were performed: clinical diagnosis was a myeloid neoplasm in 169 patients (70%), lymphoid neoplasm in 50 (21%), and unexplained cytopenia or leukocytosis in 23 (9%). The 169 myeloid cases included 59 patients with either primary (n=39) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF) myelofibrosis (n=20), 42 with acute myeloid leukemia (AML), 15 with chronic myeloid leukemia, 9 with myelodysplastic syndrome (MDS), 8 with ET, 6 with PV, and 30 with other MPDs. The 50 lymphoid cases included 19 with chronic lymphocytic leukemia, 12 with lymphoma, 11 with acute lymphocytic leukemia (ALL), and 8 with plasma cell proliferative disorders. PB cytogenetic studies resulted in at least two analyzable metaphases (median 20, range 2–31) in 142 of the 242 study cases (59%); in univariate analysis, this was predicted by the specific clinical diagnosis (p<0.0001), presence and degree of circulating myeloid progenitor cells (p<0.0001), higher leukocyte count (p<0.001), lower platelet count (p=0.003), lower hemoglobin level (p=0.002), and presence of palpable splenomegaly (p=0.002). In multivariable analysis, only the presence of circulating myeloid progenitor cells sustained its significance and this was consistent with the high yield rates seen in PMF (80%), post-PV/ET MF (85%), AML (76%), and ALL (80%) as opposed to the low rates seen in ET (0%) and PV (2%). In 104 cases, BM cytogenetic studies were performed within one month of the PB cytogenetic studies; an abnormal BM cytogenetic finding was another independent predictor of a successful PB study (p=0.002). Conclusion: PB cytogenetic studies are most appropriate in diseases characterized by presence of circulating myeloid progenitors or blasts (e.g. PMF, AML, ALL); the yield otherwise is too small to be cost-effective. The current study also suggests a higher likelihood of a successful PB cytogenetic study in the presence of an abnormal bone marrow karyotype.

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The Impact of NFAT Inhibition on Neutrophil Antifungal Defense and Myelopoiesis in Cyclosporine A Treated and NFATc1LysM Mice

Blood ◽

10.1182/blood.v126.23.1007.1007 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1007-1007

Author(s):

Daniel Teschner ◽

Christian Michel ◽

Steve Pruefer ◽

Matthias Theobald ◽

Hansjoerg Schild ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Immune Response ◽

Progenitor Cells ◽

Pulmonary Inflammation ◽

Innate Immune ◽

Myeloid Differentiation ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

Abstract Background and Aims: Immunodeficient patients after allogeneic stem cell transplantation (HSCT) are heavily threatened by opportunistic fungal infections like invasive pulmonary aspergillosis (IPA), partly due to immunosuppressive medication e.g. by calcineurin inhibitors like cyclosporine A (CsA) or tacrolimus. It is well known that the nuclear factor of activated T cells (NFAT) is an important transcription factor downstream of calcineurin in the adaptive immune system especially in T cells. Additionally, there is a growing body of evidence that NFAT also plays a substantial role in innate immune response against invasive fungal diseases by polymorphonuclear neutrophils (PMN), as well as in regulation of myelopoiesis and myeloid differentiation, as indicated by recent data in rodent models. Methods: Firstly, we used a murine IPA model (C57BL/6) to clarify the role of NFAT in antifungal innate immune response in vivo. To do so, we treated mice intraperitoneally with CsA (18mg/kg/d) or vehicle for 2 weeks and challenged them with Aspergillus fumigatus (A. f.) conidia intratracheally. 24 hours later, some mice were sacrificed and PMN recruitment to the lungs and pulmonary fungal clearance were examined by analyzing bronchoalveolar lavages (BAL) and peripheral blood (PB) by flow cytometry and murine lungs by fungal culture assays and histopathologic examination. In addition, survival of remaining infected mice was studied with neutropenic animals (by depletion with anti-Gr1) serving as positive controls. Secondly, LysM-specific NFATc1 knockout (NFATc1LysM) mice were bred lacking NFATc1 expression solely in myelomonocytic cells (i.e. PMN and monocytes). Furthermore, these animals were infected with A. f. and analyzed as described above. Secondly, we investigated myelopoiesis and myeloid differentiation under steady state conditions by quantifying bone marrow derived myeloid progenitor cells from CsA treated or NFATc1LysM mice using flow cytometry and simultaneously counting PMN in PB. Results: While the infection was lethal in CsA or vehicle treated neutropenic mice, all CsA or vehicle treated mice survived the infection. CsA treated mice showed enhanced PMN recruitment in BAL by trend (55.2% +/- 12.0 (CsA) vs. 33.7% +/- 8.0 (control), mean +/- SEM, p=0.053), whereas pulmonary inflammation and PMN counts in PB were comparable to controls. In contrast, fungal clearance was clearly impaired in animals after CsA treatment (2.1 x 105 CFU/lung after 48 hours +/- 0.5 (CsA) vs. 1.7 x 105 +/- 0.2 (control), p<0.005). Along with that, NFATc1LysM mice infected with A. f. showed unimpaired survival. However, there were no detectable differences in PMN recruitment or fungal clearance, whereas pulmonary inflammation and PMN counts in PB seemed to be more pronounced in knockout mice (1.0 inflammation points/lung +/- 0.12 (NFATc1LysM) vs. 0.7 +/- 0.07 (control), p=0.057; 1.5 x 103 PMN/µl +/- 0.2 (NFATc1LysM) vs. 0.9 +/- 0.1 (control), p=0.036). Distribution of bone marrow derived murine myeloid progenitor cells was unaffected through NFAT inhibition by CsA but clearly impaired in NFATc1LysM mice especially in megakaryocyte-erythroid progenitor cells (1.2 x 105 cells +/- 0.2 (NFATc1LysM) vs. 2.7 +/- 0.6, p=0.015) whereas PMN blood counts in PB were unchanged. Conclusions: In a mouse model, NFAT inhibition via treatment with CsA does not influence survival after infection with A. f. in vivo but affects PMN recruitment and local fungal clearance. To some extent this may be due to impaired PMN phagocytic and migratory capabilities as indicated by our in vitro and ex vivo studies (data not shown). However, solely NFATc1 downregulation in PMN apparently results in slightly different effects given that infected NFATc1LysM mice displayed enhanced pulmonary inflammation and elevated PMN blood counts compared to controls. Additionally, NFATc1 inhibition in NFATc1LysM mice leads to constrained myelopoiesis under steady state conditions without affecting peripheral PMN blood counts compared to untreated wild type controls. Further studies are needed to clarify underlying mechanisms and clinical relevance in HSCT of our findings. Disclosures No relevant conflicts of interest to declare.

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Deoxycytidine stimulates the in vitro growth of normal CFU-GM and reverses the negative regulatory effects of acidic isoferritin and prostaglandin E1

Blood ◽

10.1182/blood.v68.5.1136.1136 ◽

1986 ◽

Vol 68 (5) ◽

pp. 1136-1141 ◽

Cited By ~ 8

Author(s):

K Bhalla ◽

J Cole ◽

W MacLaughlin ◽

M Baker ◽

Z Arlin ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Prostaglandin E1 ◽

S Phase ◽

In Vitro Growth ◽

Inhibitory Effects ◽

Initial Exposure ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells

Abstract We have examined the effect of supraphysiologic concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) on the in vitro growth of normal (CFU-GM) and leukemic (L-CFU) myeloid progenitor cells. Bone marrow samples obtained from 34 consecutive patients undergoing routine diagnostic bone marrow aspirations for nonmalignant hematologic disorders exhibited nearly a twofold increment in CFU-GM when continuously cultured in the presence of 10(-4) mol/L dCyd. Higher dCyd concentrations were associated with a smaller degree of enhancement of colony formation. In contrast, the growth of leukemic blast progenitors obtained from patients with acute nonlymphocytic leukemia were not enhanced by any of the dCyd concentrations tested. Coadministration of 10(-3) mol/L tetrahydrouridine (THU), a cytidine deaminase inhibitor, failed to alter the relative inability of dCyd to enhance L-CFU colony growth. The stimulatory effect of dCyd on normal CFU-GM was not mediated by the adherent mononuclear cell population of the marrow, nor was it restricted to the subpopulation of CFU-GM in S phase at the time of initial exposure. Moreover, treatment of normal bone marrow cells with dCyd at concentrations ranging from 10(-6) to 5 X 10(-3) mol/L for 24 hours had only a minor effect on the fraction of CFU-GM in S phase. Coadministration of 10(-4) mol/L dCyd was able to reverse the inhibitory effects of several putative regulators of normal myelopoiesis, including leukemia inhibitory activity (LIA), acidic isoferritins (AIF), and prostaglandin E1 (PGE1). Leukemic myeloblasts exposed to 10(-4) mol/L dCyd exhibited substantial expansion of intracellular pools of dCyd triphosphate (dCTP), demonstrating that inability to metabolize dCyd could not be solely responsible for the absence of growth potentiation in these cells. These studies suggest that supraphysiologic concentrations of dCyd may confer a selective in vitro growth advantage upon normal v leukemic myeloid progenitor cells, and may free the former from the inhibitory effects of several potential negative regulators of myelopoiesis.

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Myeloid Progenitor Cells from Gadd45a and Gadd45b-Deficient Mice Are Sensitized to Genotoxic-Stress Induced Apoptosis.

Blood ◽

10.1182/blood.v104.11.4239.4239 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4239-4239

Author(s):

Mamta Gupta ◽

Shiv K. Gupta ◽

Arthur G. Balliet ◽

Barbara Hoffman ◽

Dan A. Lieberman

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Bone Marrow Cells ◽

Genotoxic Stress ◽

Wild Type ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells ◽

Induced Apoptosis ◽

Deficient Mice ◽

Marrow Cells

Abstract GADD45 (Growth arrest and DNA damge) regulates cell growth following exposure to diverse stimuli. It has been shown that, mice lacking the gadd45a gene exhibit genomic instability and increased carcinogenesis, but the exact role of the gadd45 family genes still remains unclear. In this study we have aimed at determining the effect of gadd45a or gadd45b deficiency on the response of bone marrow derived myeloid cells to genotoxic stress agents by using gadd45a or gadd45b null mice. We have found that myeloid progenitor cells from gadd45a or gadd45b-null mice are more sensitive to ultraviolet-radiation (UV), VP-16 or daunorubicin induced apoptosis. Introduction of wild-type gadd45 into gadd45-deficient bone marrow cells restored the wild-type apoptotic phenotype. In-vitro colony formation following stress responses has shown that bone marrow cells from gadd45a or gadd45b-deficient mice have a decreased ability to form haematopoetic colonies. Gadd45a or gadd45b-deficient bone marrow cells also displayed defective G2/M cell cycle checkpoint following exposure to either UV and V-16 but were still able to undergo G2/M arrest following exposure to daunorubicin, indicating the existence of different G2/M checkpoints in response to these anticancer agents. Taken together these findings identify gadd45a or gadd45b as anti-apoptotic gene(s), and suggests that the absence of gadd45a or gadd45b results in higher susceptibility of haematopoetic cells to UV radiation and certain anticancer drugs.

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Myc Induces Acute Myeloid Leukemia by Conferring Self-Renewal Activity to Committed Myeloid Progenitor Cells That Resist Apoptosis Via Endogenous Mcl-1.

Blood ◽

10.1182/blood.v110.11.2634.2634 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2634-2634

Author(s):

Hui Luo ◽

Jennifer A. Cain ◽

AnnaLynn Molitoris ◽

Joseph Opferman ◽

Michael H. Tomasson

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Median Survival ◽

Myeloid Leukemia ◽

Bone Marrow Cells ◽

Ectopic Expression ◽

Hematopoietic Stem ◽

Myeloid Progenitor ◽

Myeloid Progenitor Cells ◽

Induced Apoptosis

Abstract Ectopic expression of Myc in most primary cell types induces apoptosis, and cancer development typically requires additional, anti-apoptotic mutations. We reported previously that ectopic expression of Myc in unfractionated murine bone marrow cells induced rapid onset acute myeloid leukemia (AML) without detectable anti-apoptotic mutations. We hypothesized that AML developed in our model because a subset of normal primary bone marrow cells were inherently resistant to Myc-induced apoptosis. Consistent with this model, seven days of Myc activation in the bone marrow of mice caused the reduction of B-lineage cells while at the same time inducing the expansion of myeloid lineage cells. We sought to determine the mechanism by which myeloid progenitor cells evaded Myc-induced apoptosis, and found that Myc-induced AML cells exhibited a distinct profile of pro- and anti-apoptotic proteins, including high levels of the anti-apoptotic Bcl-2 family member Mcl-1. To prioritize apoptosis genes, we examined AML patient microarray data and found MCL1 to be uniformly expressed at high levels in human AML (94/94, 100%). We used Mcl1 heterozygous mice (Mcl1F/null) as bone marrow donors for transduction-transplantation experiments and found that, compared with Mcl1 wild-type (median survival=60 days), haploinsufficiency for Mcl1 completely protected mice from Myc-induced AML (median survival not reached). Mice transplanted with Mcl1F/null cells co-expressing Myc and Bcl2 succumbed rapidly to disease (median survival 25 days). In wild-type mice, defined hematopoietic stem and myeloid progenitor cell populations were not significantly increased by Myc activation. However, Myc transduction conferred serial replating ability to sorted hematopoietic stem and progenitor cells including lineage-committed (Lin+Kit+) progenitors cells. These data demonstrate a critical role for Mcl1 in our AML model and suggest that dysregulation of MYC in MCL1-expressing progenitor cells may mediate AML pathogenesis in humans.

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