scholarly journals Constitutive Activation of Shp2 Cooperates with MLL1 Fusion Proteins to Increase Expression of the Homeodomain Transcription Factors Cdx4, HoxA9 and HoxA10

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3537-3537
Author(s):  
Ling Bei ◽  
Chirag Shah ◽  
Hao Wang ◽  
Elizabeth Eklund
Keyword(s):  
Transcription Factors ◽  
Progenitor Cells ◽  
Tyrosine Phosphorylation ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Constitutive Activation ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Homeodomain Transcription Factors ◽  
Constitutively Active

Abstract Leukemias with chromosomal translocation or partial tandem duplications involving the MLL (mixed lineage leukemia) gene have exceptionally poor prognosis (referred to as 11q23-leukemias). At the molecular level, 11q23-leukemias are characterized by aberrant expression of a set of homeodomain transcription factors in hematopoietic stem cells (HSC) and differentiating myeloid progenitor cells. This transcription factor set includes HoxB3, B4, A7-11, Cdx2-4 and Meis1. Cdx and Hox proteins are involved in regulating hematopoiesis. Transcription of HOX and CDX genes decreases normal myelopoiesis, but is aberrantly sustained in 11q23-leukemias. Cdx4 activates transcription of the HOXA9 and HOXA10 genes, and HoxA10 activates CDX4 transcription. The events that break this feedback loop, permitting a decrease in Cdx4-expression during normal myelopoiesis, were previously undefined. In the current study, we find that HoxA9 represses CDX4 transcription in differentiating myeloid cells; antagonizing activation by HoxA10. We determine that tyrosine phosphorylation of HoxA10 impairs transcriptional activation of CDX4, but tyrosine phosphorylation of HoxA9 facilitates repression of this gene. Since HoxA9 and HoxA10 are phosphorylated during myelopoiesis, this provides a mechanism for differentiation-stage-specific Cdx4 expression. HoxA9 and HoxA10 are increased in cells expressing Mll-Ell, a leukemia associated MLL1 fusion protein. We find that Mll-Ell induces a HoxA10-dependent increase in Cdx4-expression in myeloid progenitor cells. However, expression of Cdx4 decreases in a HoxA9-dependent manner upon exposure of Mll-Ell-expressing cells to differentiating cytokines. Leukemia associated, constitutively active mutants of Shp2 block cytokine-induced tyrosine phosphorylation of HoxA9 and HoxA10. In comparison to cells expressing Mll-Ell alone, we find that co-expression of Mll-Ell plus constitutively active Shp2 increases CDX4 transcription and Cdx4 expression in myeloid progenitor cells. And, increased Cdx4 expression is sustained upon exposure of these cells to differentiating cytokines. Our results identify a mechanism for increased and sustained CDX4 transcription in leukemias co-overexpressing HoxA9 and HoxA10 in combination with constitutive activation of Shp2. We also demonstrate that inhibition of Shp2-PTP activity decreases Cdx4 expression in Hox-overexpressing human myeloid leukemias. Disclosures No relevant conflicts of interest to declare.

Abstract 20010: Diet-induced Obesity Stimulates Inflammatory Monopoiesis From Hematopoietic Stem Progenitor Cells Through Activating Histone Methylation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Milie Fang ◽  
Rita Mirza ◽  
Timothy J Koh ◽  
Norifumi Urao
Keyword(s):  
Progenitor Cells ◽  
Fold Increase ◽  
Control Mechanisms ◽  
Hematopoietic Stem ◽  
Fluorescent Intensity ◽  
Inflammatory Monocytes ◽  
Diet Induced Obesity ◽  
Histone 3 ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Obesity-induced monopoiesis has been implicated in the development of obesity-related complications. Monopoiesis is largely dependent on hematopoietic stem progenitor cells (HSPCs) in the bone marrow (BM). However, little is known about hematopoietic control mechanisms in diet-induced obesity. In a mouse model of diet-induced obesity (DIO), we found leukocytosis (9.465 ± 0.7350 K/ul versus 7.277 ± 0.3450 K/ul in healthy controls, n=7 each? , p=0.023) and increased inflammatory Ly6Chi monocytes in circulation (377.2 ± 40.94/ul vs. 224.8 ± 39.18/ul in lean control; n=7; p=0.023), associated with increased myeloid progenitor cells (60% increase in granulocyte-monocyte progenitor cells, n=4) in the BM. By flow cytometry based profiling, we found that active marks for transcription, histone 3 lysine 4 trimethylation (H3K4me3), are upregulated (1.82-fold increase in mean fluorescent intensity (MFI) vs. lean mice, n=5, p<0.05) in Ly6Chi inflammatory monocytes in DIO mice, along with increased inflammatory gene expression in response to TLR (toll-like receptor) 4 stimulation. In the BM, HSPCs but not myeloid progenitor cells have enriched H3K4me3 in DIO mice (2.84-fold in MFI in cKit+Sca1+Lin- cells, n=5, p<0.05). This activated mark in HSPCs is associated with increased monopoiesis from HSPCs (1.55-fold increase in output CD11b+Ly6Chi monocytes from cultured HSPCs, n=3-5, p<0.01) in response to TLR2 and TLR4 stimulations. Of note, HSPCs produce inflammatory cytokines to promote differentiation into inflammatory monocytes. Moreover, HIF-1a, a potential upstream of H3K4me3, is upregulated (2.29-fold in MFI, n=5, p<0.05) in HSPCs in DIO mice. These results suggest that obesity increases HIF-1a-mediated H3K4me3 enrichment in HSPCs, which in turn contributes to inflammatory cytokine expression and to increased inflammatory monopoiesis. Thus, epigenetic marks in HSPCs could be a target for obesity-related complications.

scholarly journals 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 ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2229-2236 ◽  
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.

HoxA10 Regulates Myeloid Progenitor Proliferation by Activating Transcription of the Gene Encoding Transforming Growth Factor Beta 2.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1572-1572
Author(s):  
Chirag Shah ◽  
Hao Wang ◽  
Elizabeth A. Eklund
Keyword(s):  
Progenitor Cells ◽  
Transforming Growth Factor Beta ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Growth Factor Beta ◽  
Differentiation Block

Abstract Abstract 1572 HoxA10 is a homeodomain transcription factor which functions as a myeloid leukemia promoter. Correlative clinical studies found that increased expression of a group of HoxA proteins, including HoxA10, in acute myeloid leukemia (AML) was associated with poor prognosis. In murine models, overexpression of HoxA10 in the bone marrow was associated with development of a myeloproliferative disease which progressed to AML with time. These results suggested that HoxA10-overexpression dysregulated cell proliferation and/or survival, and predisposed to acquisition of additional mutations which led to differentiation block and AML. Additional investigations, we and others demonstrated that HoxA10 overexpression in murine hematopoietic stem cells (HSC) expanded the granulocyte/monocyte progenitor (GMP) population in vitro and in vivo. Despite this information about the impact of HoxA10 overexpression on myeloid leukemogenesis, the mechanisms by which HoxA10 exerts this effect are largely unknown. To investigate such mechanisms, we have been identifying HoxA10 target genes. In previous studies, we identified a number of HoxA10 target genes that encode phagocyte effector proteins. HoxA10 represses transcription of these gene in myeloid progenitors, and decreased HoxA10 repression activity contributes to phenotypic differentiation as myelopoiesis proceeds. This provided a potential mechanism for HoxA10 involvement in differentiation block, but not progenitor survival or expansion. We used a chromatin immuno-precipitation based approach to identify additional HoxA10 target genes involved in these activities. Previously, we reported that HoxA10 activated the DUSP4 gene in myeloid progenitor cells. This gene encodes Mitogen Activated Protein Kinase Phosphatase 2 (Mkp2) which inhibits Jnk-induced apoptosis in myeloid progenitor cells. This provided a mechanism for increased cell survival in HoxA10-overexpressing cells. In the current studies, we identified TGFB2 as a HoxA10 target gene. This gene encodes Transforming Growth Factor Beta 2 (TgfB2) a member of the TgfB super family of cytokines. Similar to TgfB1 and 3, TgfB2 interacts with TgfB-receptors I and II. However, unlike these more classical family members, TgfB2 induces proliferation of hematopoietic stem and progenitor cells. We found that HoxA10 activated the TGFB2 promoter via tandem cis elements in the proximal promoter. This resulted in autocrine stimulation of proliferation in HoxA10-overexpressing GMP and leukemia cells in vitro. Increased proliferation in HoxA10-overexpressing cells involved activation of the MAP kinase pathway in a TgfB2 dependent manner. These studies identify autocrine production of pro-proliferative cytokines as a novel mechanism for the function of Hox proteins. These findings have implications for ex vivo expansion of HSC and myeloid progenitors for tissue engineering. These result also have implications for therapeutic approaches to poor prognosis AML characterized by increased Hox expression. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
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.

Neutropenic Mice Can Be Protected from Fungus Infection by Ex Vivo Expanded Allogeneic Myeloid Progenitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3038-3038
Author(s):  
Jos Domen ◽  
Mastura Wahedi ◽  
Esther Danenberg ◽  
Stephanie Smith-Berdan ◽  
Julie Christensen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Hematopoietic Cell Transplantation ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Large Numbers ◽  
Myeloid Progenitor Cells ◽  
Myeloid Progenitors

Abstract Neutropenia induced by chemotherapy, hematopoietic cell transplantation, as well as radiation-induced neutropenia is accompanied by a significant morbidity and mortality due to increased susceptibility to a variety of pathogens. Despite clinical advances, such as the availability of growth factors that can stimulate granulopoiesis, like G-CSF, and new generations of antibiotics and antifungal agents, the problem persists. Direct cellular therapy with mature granulocytes has met with limited success, and would be difficult to implement due to the large number of cells needed, their very short lifespan and the inability to store the cells between harvesting and use. Our long-term goal is to develop a non-HLA-restricted cell-based short-term bridging therapy to reduce susceptibility to infection and enhance recovery from infections in the setting of neutropenia. The recent characterization of surface marker profiles of early myeloid progenitors has allowed the prospective testing of these cells. It has been clearly shown that the use of limited numbers of a combination of Common Myeloid Progenitors (CMP) and Granulocyte-Macrophage-Progenitors (GMP), purified from bone marrow, can protect mice from a normally lethal challenge with fungus or bacteria [Blood100:4660-7(2002)]. We have extended these observations and tested whether myeloid progenitors (MP) with similar properties can be obtained in large numbers from hematopoietic stem cells (HSC) in vitro. Here we report that a one week, serum-free culture can result in a 200-fold expansion of cells with myeloid progenitor activity with respect to the starting CD117+, CD90.1low, Linneg/low and Sca-1+ KTLS-HSC. Furthermore, these myeloid progenitor cells are as effective as Myeloid Progenitors sorted directly from bone marrow in preventing death due to invasive aspergillosis, even when the cells are fully allogeneic and have been cryopreserved prior to use. These results indicate a way in which myeloid progenitor cells, which can be stored frozen prior to use, can be obtained in large numbers. This process, once translated to human cells, would also open the way for the stockpiling of MP for use in nuclear disasters.

Bcr/Abl Increases Bcatenin Protein and Activity in An ICSBP-Dependent Manner in Myeloid Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2958-2958
Author(s):  
Weiqi Huang ◽  
Elizabeth Horvath ◽  
Elizabeth A. Eklund
Keyword(s):  
Bone Marrow ◽  
Tumor Suppressor ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Dependent Manner ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract Abstract 2958 Poster Board II-934 The interferon consensus sequence binding protein (ICSBP) is an interferon regulatory transcription factor (also referred to as IRF8). Similar to other IRF proteins, ICSBP regulates transcription of genes involved in the inflammatory response. However, ICSBP also functions as a myeloid leukemia tumor suppressor. Specifically, decreased ICSBP expression in myeloid progenitor cells results in cytokine hypersensitivity and resistance to apoptosis in response to Fas-activation or IL3 withdrawal. Consistent with function as a tumor suppressor, decreased ICSBP-expression is found in the bone marrow of human subjects with chronic myeloid leukemia (CML). Expression of ICSBP increases during remission and decreasing ICSBP expression is associated with progression to CML blast crisis (BC). In murine models, ICSBP-deficiency induces a myeloproliferative disorder (MPD) which resembles CML. And, ICSBP overexpression blocks MPD in mice transplanted with Bcr/abl expressing bone marrow. Increased Bcatenin activity is also associated with CML-BC. However, the impact of ICSBP on Bcatenin expression or activity has not been previously investigated. In these studies, we hypothesized that ICSBP-deficiency in CML-BC increases Bcatenin-expression. In support of this hypothesis, we found that Bcatenin protein and activity were increased in myeloid cell lines with ICSBP-knock-down and decreased in cells with ICSBP-overexpression. Bcatenin protein and activity were also increased in primary myeloid progenitors from ICSBP-/- mice in comparison to wild type or ICSBP+/- mice, in an ICSBP-dose dependent manner. Expression of Bcr/abl decreased ICSBP-expression in myeloid cells and increased Bcatenin protein and activity. Also supporting our hypothesis, the effect of Bcr/abl on Bcatenin was abolished by re-expression of ICSBP in Bcr/abl expressing myeloid cell lines or primary murine myeloid progenitor cells. In each of these situations, the increase in Bcatenin protein was not due to increased expression of Bcatenin mRNA. These results suggest ICSBP influences expression of target genes involved in Bcatenin protein stability. Therefore, these studies identify a pathway by which Bcr/abl activity impairs ICSBP expression in immature myeloid cells, thereby increasing stability of Bcatenin protein and Bcatenin activity. Poor prognosis and BC are associated with Fas resistance and increased Bcatenin activity in CML leukemia stem cells (LSC). Bcr/abl activity is also associated with decreased expression of ICSBP. Our prior studies implicated ICSBP-deficiency in Fas-resistance in CML via the ICSBP target gene PTPN13. Our current studies implicate ICSBP-deficiency in increased Bcatenin expression in CML. These results suggest that decreased ICSBP expression drives multiple aspects of the poor prognosis LSC phenotype in CML. Disclosures: No relevant conflicts of interest to declare.

A Constitutively-Active ABL Family Kinase, TEL-ARG, Induces Lethal Mastocytosis through Sensitizing Hematopoietic Stem/Progenitor Cells to IL-3

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2828-2828
Author(s):  
Asumi Yokota ◽  
Hideyo Hirai ◽  
Tsukimi Shoji ◽  
Taira Maekawa ◽  
Keiko Okuda
Keyword(s):  
Mast Cell ◽  
Cell Differentiation ◽  
Mast Cells ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Myeloid Differentiation ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Terminal Domain ◽  
Constitutively Active

Abstract ABL family kinases, ABL1 (ABL) and ABL2 (ARG), share functional domains such as SH2-, SH3- and kinase domains, and are highly homologous except their C-terminal domain. Fusions to TEL (ETV6), TEL-ABL and TEL-ARG, are constitutively-active kinases and have been reported in rare cases of human CML, AML or ALL. Although TEL-ABL is involved in leukemogenesis, the role of TEL-ARG has not been elucidated because this fusion protein has been always accompanied with other major translocations, such as PML-RARα. We have previously shown that although their kinase activities are comparable, TEL-ABL strongly transforms Ba/F3 cells, while TEL-ARG has a much lower transforming activity, and these differences are attributed to their distinct C-terminal domain (Okuda K and Hirai H, Open Journal of Blood Diseases 2013). At the last ASH annual meeting, we have shown that TEL-ABL induces myeloid leukemia in a short latency, whereas TEL-ARG induces lethal mastocytosis in a long latency in a mouse bone marrow (BM) transplantation model (Abstract number #2368, ASH 2014). Here we investigated the clonogenicity of mastocytosis and explored the detailed mechanism underlying the onset of mastocytosis induced by TEL-ARG. First, we performed a serial transplantation experiment to evaluate mastocytosis-initiating capacity of TEL-ARG-expressing cells. Hematopoietic stem/progenitor cells (HSPCs) from 5-FU-treated mice were retrovirally transduced with TEL-ARG and transplanted to the first recipient mice. BM cells from moribund mice due to mastocytosis were transplanted to the sublethally irradiated second recipients. On day 219 after transplantation, we detected mast cells circulating in the peripheral blood of these two recipients, and observed severe pancytopenia and body weight loss in one of them. In this mouse, mast cells engulfing blood cells were accumulated in the BM and spleen, and subcutaneous tissues were massively infiltrated by mast cells, all of which were characteristics of mastocytosis observed in the first recipients. These results indicate that TEL-ARG confers mastocytosis-initiating capacity on HSPCs. Next, we focused on the mechanisms why TEL-ARG induces mastocytosis, whereas TEL-ABL induces myeloid leukemia. HSPCs from 5-FU-treated mice were retrovirally transduced with TEL-ABL or TEL-ARG, and subjected to the in vitro mast cell differentiation assay in the presence of WEHI-conditioned medium, as a source of IL-3 (Figure). IL-3 enhanced differentiation and proliferation of empty-virus-transduced HSPCs toward mast cells in a dose-dependent manner. TEL-ARG induced mast cell differentiation in the absence of IL-3 to some extent, and IL-3 markedly increased mast cell number even at a lower concentration. TEL-ARG-expressing mast cells continue to proliferate for more than 4 months maintaining their phenotype as mast cells. In contrast, IL-3 did not enhance mast cell differentiation but support myeloid differentiation of TEL-ABL-expressing HSPCs. These data suggest that while TEL-ABL induces myeloid differentiation, TEL-ARG strongly promotes differentiation toward mast cells through sensitizing HSPCs to IL-3, an important factor for differentiation, survival and proliferation of mast cells. Furthermore, these results might account for differences in the phenotypes of diseases induced by TEL-ABL (myeloid leukemia) or TEL-ARG (mastocytosis). In conclusions, TEL-ABL strongly induces myeloid-skewed differentiation, whereas TEL-ARG promotes mast cell differentiation through increasing sensitivity to IL-3 and induces clonal mast cell disease. We are currently investigating the molecular mechanisms by which they activate distinct differentiation pathways toward myeloid cells or mast cells. We believe that further exploration of the underlying mechanisms will deepen our understanding of the molecular basis for ABL kinase-mediated leukemogenesis as well as mast cell disorders. Disclosures No relevant conflicts of interest to declare.

scholarly journals Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2583-2587 ◽  
Author(s):  
AL Petzer ◽  
R Bilgeri ◽  
U Zilian ◽  
M Haun ◽  
FH Geisen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
T Lymphocyte ◽  
Human Lymphocytes ◽  
Maturation Stage ◽  
Dependent Manner ◽  
Myeloid Progenitor ◽  
Marked Inhibition ◽  
Myeloid Progenitor Cells

Abstract Previous studies have shown that 2-chloro-2′-deoxyadenosine (CdA) is markedly toxic to normal and malignant human lymphocytes in vitro and in vivo. Recent clinical trials have shown that CdA is a very promising drug for the treatment of lymphoid malignancies. The present investigations were designed to test the effect of CdA on the in vitro clonal growth of both myeloid progenitors and T-lymphocyte colony- forming cells (CFU-TL) obtained from normal human bone marrow and peripheral blood. Cells were exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of CdA mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone marrow cells were used for our investigations. The results show a marked inhibition of myeloid progenitor and lymphocyte colony-forming cells in a dose-dependent manner, correlating with maturation stage in that the immature progenitor cells are more sensitive to this drug. Furthermore, our studies suggest that a sequence of metabolic events previously described for lymphocytes may be operative in myeloid progenitor cells because a minimal exposure time of 48 hours is required to obtain a marked inhibition. CdA toxicity was proposed to be linked with phosphorylation by deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found to be high in lymphocytes, but low in granulocytes. However, the marked inhibition of myeloid progenitor cells shown in these studies suggests that other factors such as modulation of the effect of CdA by the ambient levels of other deoxynucleosides might influence the apparent sensitivity of myeloid cells.

scholarly journals The Histone Chaperone CAF-1 Sustains Myeloid Lineage Identity

2020 ◽  
Author(s):  
Yiming Guo ◽  
Fei Ji ◽  
Jernej Murn ◽  
David Frankhouser ◽  
M Andres Blanco ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Progenitor Cells ◽  
Chromatin Accessibility ◽  
Differentiation Potential ◽  
Myeloid Lineage ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Stem And Progenitor Cells ◽  
Assembly Factor

AbstractDuring hematopoiesis, stem and progenitor cells become progressively restricted in their differentiation potential. This process is driven by lineage-specific transcription factors and is accompanied by dynamic changes in chromatin structure. The chromatin assembly factor complex CAF-1 is a key regulator of cellular plasticity in various cell lineages in different organisms. However, whether CAF-1 sustains lineage identity during normal homeostasis is unclear. To address this question, we investigated the role of CAF-1 in myeloid progenitor cells. CAF-1 suppression in myeloid progenitors triggered their rapid commitment but incomplete differentiation toward granulocyte, megakaryocyte, and erythrocyte lineages, resulting in a mixed cellular state. Through comparison with a canonical paradigm of directed terminal myeloid differentiation, we define changes in chromatin accessibility that underlie a unique transcriptome of the aberrantly matured CAF-1 deficient cells. We further identify C/EBPα and ELF1 as key transcription factors whose control of myeloid lineage commitment is kept in check by CAF-1. These findings shed new light on molecular underpinnings of hematopoiesis and suggest that manipulation of chromatin accessibility through modulating CAF-1 levels may provide a powerful strategy for controlled differentiation of blood cells.

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