Transgene Insertion into the Proximity of the c-myb Gene Disrupts Erythroid-Megakaryocytic Lineage Bifurcation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1172-1172
Author(s):  
Harumi Yamamoto Mukai ◽  
Hozumi Motohashi ◽  
Toshiro Nagasawa ◽  
Masayuki Yamamoto
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Erythropoietin Receptor ◽  
Mutant Mice ◽  
Upstream Region ◽  
Myb Gene ◽  
Homozygous Mutant ◽  
Transgene Insertion ◽  
Marrow Cells

Abstract The nuclear proto-oncogene c-myb plays crucial roles in the growth, survival and differentiation of hematopoietic cells. We established three lines of erythropoietin receptor transgenic mice and found that one of them exhibited anemia, thrombocythemia and splenomegaly. These abnormalities were independent of the function of the transgenic erythropoietin receptor, and were observed exclusively in mice harboring the transgene homozygously, suggesting transgenic disruption of a certain gene. The transgene was inserted 77-kb upstream of the c-myb gene and c-Myb expression was markedly decreased in megakaryocyte-erythrocyte lineage-restricted progenitors (MEPs) of the homozygous mutant mice. In the bone marrows and spleens of the mutant mice, megakaryocytes were increased, but erythroid progenitors were decreased. These abnormalities were reproducible in vitro in a co-culture assay of MEPs with OP9 cells, but eliminated by the retroviral expression of c-Myb in MEPs. The erythroid-megakaryocytic abnormalities were reconstituted in mice in vivo through the transplantation of mutant mouse bone marrow cells. To better understand the transcriptional program that accompanies the decline of c-myb gene expression, we performed DNA microarray analysis of MEPs. We identified 74 genes that are upregulated and 36 genes are downregulated in the homozygous mutant mice. Of these genes, expression levels 10 genes are actually changed in bone marrow cells of the homozygous mutant mice, and harbor c-Myb recognition elements in the upstream region. These results thus demonstrate that the transgene insertion into the c-myb gene far upstream regulatory region affects the gene expression at the stage of MEPs, leading to an imbalance between erythroid and megakaryocytic cells, and suggest that c-Myb is an essential regulator of the erythroid-megakaryocytic lineage bifurcation. Elucidation of transcription network based on the c-myb gene in erythroid and megakaryocytic lineages will take a new turn of lineage specific regulation. Figure Figure

scholarly journals Transgene Insertion in Proximity to thec-myb Gene Disrupts Erythroid-Megakaryocytic Lineage Bifurcation

2006 ◽  
Vol 26 (21) ◽  
pp. 7953-7965 ◽  
Author(s):  
Harumi Y. Mukai ◽  
Hozumi Motohashi ◽  
Osamu Ohneda ◽  
Norio Suzuki ◽  
Masumi Nagano ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Regulatory Region ◽  
Erythropoietin Receptor ◽  
Mutant Mice ◽  
Mouse Bone Marrow ◽  
Erythroid Progenitors ◽  
Myb Gene ◽  
Transgene Insertion

ABSTRACT The nuclear proto-oncogene c-myb plays crucial roles in the growth, survival, and differentiation of hematopoietic cells. We established three lines of erythropoietin receptor-transgenic mice and found that one of them exhibited anemia, thrombocythemia, and splenomegaly. These abnormalities were independent of the function of the transgenic erythropoietin receptor and were observed exclusively in mice harboring the transgene homozygously, suggesting transgenic disruption of a certain gene. The transgene was inserted 77 kb upstream of the c-myb gene, and c-Myb expression was markedly decreased in megakaryocyte/erythrocyte lineage-restricted progenitors (MEPs) of the homozygous mutant mice. In the bone marrows and spleens of the mutant mice, numbers of megakaryocytes were increased and numbers of erythroid progenitors were decreased. These abnormalities were reproducible in vitro in a coculture assay of MEPs with OP9 cells but eliminated by the retroviral expression of c-Myb in MEPs. The erythroid/megakaryocytic abnormalities were reconstituted in mice in vivo by transplantation of mutant mouse bone marrow cells. These results demonstrate that the transgene insertion into the c-myb gene far upstream regulatory region affects the gene expression at the stage of MEPs, leading to an imbalance between erythroid and megakaryocytic cells, and suggest that c-Myb is an essential regulator of the erythroid-megakaryocytic lineage bifurcation.

Murine pluripotent hematopoietic progenitors constitutively expressing a normal erythropoietin receptor proliferate in response to erythropoietin without preferential erythroid cell differentiation

1994 ◽  
Vol 14 (7) ◽  
pp. 4834-4842
Author(s):  
A Dubart ◽  
F Feger ◽  
C Lacout ◽  
F Goncalves ◽  
W Vainchenker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Erythropoietin Receptor ◽  
Erythroid Cell ◽  
Major Influence ◽  
Proliferative Potential ◽  
Steel Factor ◽  
Interleukin 3 ◽  
Marrow Cells

Erythropoietin (EPO) is a prime regulator of the growth and differentiation of erythroid blood cells. The EPO receptor (EPO-R) is expressed in late erythroid progenitors (mature BFU-E and CFU-E), and EPO induces proliferation and differentiation of these cells. By introducing, with a retroviral vector, a normal EPO-R cDNA into murine adult bone marrow cells, we showed that EPO is also able to induce proliferation in pluripotent progenitor cells. After 7 days of coculture with virus-producing cells, bone marrow cells were plated in methylcellulose culture in the presence of EPO, interleukin-3, or Steel factor alone or in combination. In the presence of EPO alone, EPO-R virus-infected bone marrow cells gave rise to mixed colonies comprising erythrocytes, granulocytes, macrophages and megakaryocytes. The addition of interleukin-3 or Steel factor to methylcellulose cultures containing EPO did not significantly modify the number of mixed colonies. The cells which generate these mixed colonies have a high proliferative potential as shown by the size and the ability of the mixed colonies to give rise to secondary colonies. Thus, it appears that EPO has the same effect on EPO-R-expressing multipotent cell proliferation as would a combination of several growth factors. Finally, our results demonstrate that inducing pluripotent progenitor cells to proliferate via the EPO signaling pathway has no major influence on their commitment.

scholarly journals Expression of Shelterin ComponentPOT1Is Associated with Decreased Telomere Length and Immunity Condition in Humans with Severe Aplastic Anemia

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Ting Wang ◽  
Shu-chong Mei ◽  
Rong Fu ◽  
Hua-quan Wang ◽  
Zong-hong Shao
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Telomere Length ◽  
Bone Marrow Cells ◽  
Culture Media ◽  
Telomere Attrition ◽  
High Concentrations ◽  
Relationship Of ◽  
The Relationship ◽  
Marrow Cells

Abnormal telomere attrition has been found to be closely related to patients with SAA in recent years. To identify the incidence of telomere attrition in SAA patients and investigate the relationship of telomere length with clinical parameters, SAA patients(n=27)and healthy controls(n=15)were enrolled in this study. Telomere length of PWBCs was significantly shorter in SAA patients than in controls. Analysis of gene expression of Shelterin complex revealed markedly low levels ofPOT1expression in SAA groups relative to controls. No differences in the gene expression of the other Shelterin components—TRF1,TRF2,TIN2,TPP1, andRAP1—were identified. Addition of IFN-γto culture media induced a similar fall in POT1 expression in bone marrow cells to that observed in cells cultured in the presence of SAA serum, suggesting IFN-γis the agent responsible for this effect of SAA serum. Furthermore, ATR, phosphorylated ATR, and phosphorylated ATM/ATR substrate were all found similarly increased in bone marrow cells exposed to SAA serum, TNF-α, or IFN-γ. In summary, SAA patients have short telomeres and decreased POT1 expression. TNF-αand IFN-γare found at high concentrations in SAA patients and may be the effectors that trigger apoptosis through POT1 and ATR.

Tel-PDGFβR Specifically Induces Interferon-Stimulated Genes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1213-1213
Author(s):  
Hani Kim ◽  
Dwayne L. Barber
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Bone Marrow ◽  
Fusion Protein ◽  
Signaling Pathways ◽  
Bone Marrow Cells ◽  
Chromosomal Translocations ◽  
Time Points ◽  
Interferon Stimulated Genes ◽  
Marrow Cells

Abstract Chromosomal translocations involving tyrosine kinases play a significant role in human leukemia. Chronic myeloid leukemia (CML) is associated with the recurrent chromosomal translocation, BCR-ABL (t(9;22)(q34;q11)). Chronic myelomonocytic leukemia (CMML) is linked to TEL-PDGF-β Receptor (PDGFβR) (t(5;12)(q33;p13)) fusion. Another TEL fusion, TEL-JAK2 (t(9;12)(p24;p13) has been observed in CMML and Acute Lymphoid Leukemia. All three fusion proteins induce leukemia-like diseases in animal models, and this is attributed to the constitutive tyrosine kinase activity, which leads to dysregulation of their respective downstream signaling pathways. The downstream targets include STAT transcription factors, MAP kinases, and PI3 kinase. On the other hand, little is known about the gene transcription regulated by these fusions. The objective of our study is to determine whether BCR-ABL, TEL-PDGFβR and TEL-JAK2 induce distinct gene expression patterns when expressed in cell lines and retrovirally transduced bone marrow cells. Each fusion was expressed in an IL3-dependent murine myeloid cell line, Ba/F3. The specific inhibitor, Imatinib mesylate, was utilized to control the activation/inhibition of BCR-ABL and TEL-PDGFβR, and an inducible system was utilized for TEL-JAK2. Upon activation of the fusion protein, cells were collected at various time-points for cell cycle and microarray analysis (Affymetrix MOE430A). We utilized 8 hr, 12 hr, 24 hr and 1 wk time points. Our rationale was to monitor gene expression changes through the first cell cycle and then to examine the fingerprint at a steady state point. Analysis of the 1 wk data reveals that a subset of genes are co-regulated (2-fold, p<0.05) by BCR-ABL, TEL-PDGFβR and TEL-JAK2 (Pim1, Id1b, Podxl, Cxcr4, Gp49b and Scin). Interestingly, analysis of the TEL-PDGFβR induced genes (10-fold, p<0.05) revealed a significant overlap with Interferon-Stimulated Gene (ISG) dataset including Cxcl-10, Gbp1, Gbp2, Isg20, Ccl-5, Stat1, Irf7, Serpine-1 and Mx1. Genes identified in this microarray study have been confirmed by Q-PCR in Ba/F3 cells and confirmatory experiments in primary bone marrow cells transduced with each fusion protein are underway. In addition, we will determine whether the transcription of these targets is dependent on STAT1 by utilizing bone marrow cells from STAT1−/− mice. In conclusion, our data reveals that oncogenic chromosomal translocations activate both distinct and co-regulated gene expression and reveal a novel and specific role of Interferon-Stimulated Genes in signaling pathways downstream of TEL-PDGFβR.

Gene Expression Changes in Bone Marrow Cells from Diamond-Blackfan Anemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 720-720 ◽  
Author(s):  
Hanna T. Gazda ◽  
Despina Sanoudou ◽  
Alvin T. Kho ◽  
Jan M. Zaucha ◽  
Colin A. Sieff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Ribosomal Protein ◽  
Cell Population ◽  
Bone Marrow Cells ◽  
Principal Component ◽  
Fold Change ◽  
Ribosomal Protein Genes ◽  
Diamond Blackfan Anemia ◽  
Marrow Cells

Abstract Diamond-Blackfan anemia is usually characterized by anemia, absence or insufficiency of erythroid precursors in bone marrow, growth retardation and diverse congenital anomalies that are present in approximately half of patients, indicating that DBA is a broad disorder of development. Mutations of RPS19 are found in approximately 25% of DBA patients. There is good evidence for a second DBA gene, located on chromosome 8, and further genetic heterogeneity of the disease is likely. The aim of this study is to determine the most disturbed molecular pathways in DBA patients, based on gene expression changes in bone marrow cells. Knowing these pathways will possibly enable us to decipher the pathogenic mechanisms of DBA and find other genes involved in the disease. Bone marrow cells from 6 normal individuals and 3 DBA patients with RPS19 mutations, currently in remission, were FACS separated into 3 populations: primitive (P), erythroid (E) and myeloid (M) containing CD34+CD71-CD45RA-, CD34+CD71hiCD45RA- and CD34+CD71lowCD45RA+ cells, respectively. The purity of each sorted population was >97%. As a control for cell sorting accuracy, methylcellulose assay demonstrated that the P populations were highly enriched in primitive BFU-E and CFU-GEMM colonies, the E populations gave rise to BFU-E and CFU-E colonies in more than 90% of the CFCs, while more than 99% colonies from M populations were CFU-G, CFU-M and CFU-GM. RNA targets from these three FACS sorted cellular subsets was hybridized to Affymetrix HG-U133A chips (>22,000 probe sets). The data from all 27 samples were analyzed by hierarchical clustering and Principal Component Analysis, and each cell population was also studied separately. All pairwise comparisons among 27 datasets showed correlations with r=0.86–0.99. Hierarchical clustering identified three major specimen clusters, perfectly overlapping with the three different cell populations under study. Principal Component 1 and 2 separated the three studied subgroups P, E, and M. In each cell population analysis, 3 patient samples were compared to 6 control samples using 1)Significance Analysis of Microarrays with fold change 2 or greater and false discovery rate 1%, 2)Geometric Fold Change analysis and 3)Filter on Fold Change GeneSpring application (arithmetic analysis). All fold change analyses revealed the most significantly changed transcripts in patients vs. control individuals in E (45 upregulated and 184 downregulated) and P populations. The most changed genes in E subgroup were apoptosis related genes, namely TNFRSF10B and TNFRSF6 (CD95/Fas), upregulated in patients 10 and 3 fold, respectively. Other most changed genes were cancer related and genes involved in developmental processes and nucleic acid binding. Additionally, several ribosomal protein genes, namely RPL10L, RPL28, RPL36, RPL13, RPL27a and RPL37a were significantly underexpressed in P and E populations of DBA patients. All three analyses showed that RPL10L, RPL28 and RPL36 are underexpressed in the M population. This finding indicates that ribosomal protein genes are closely co-regulated and that RPS19 protein abnormalities result in downregulation of the additional ribosomal protein genes in both erythroid and nonerythroid cells in DBA patients.

c-Myb Regulates CD9 Gene Expression during Megakaryopoiesis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1245-1245
Author(s):  
Harumi Y. Mukai ◽  
Tomoko Kono ◽  
Hozumi Motohashi ◽  
Masayuki Yamamoto ◽  
Hiroshi Kojima
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Luciferase Reporter ◽  
Insertion Mutagenesis ◽  
Null Mouse ◽  
Steady State Condition ◽  
Myb Gene ◽  
Genes Expression ◽  
Recognition Elements

Abstract The nuclear proto-oncogene c-myb plays crucial roles in the growth, survival, and differentiation of hematopoietic cells. We previously generated through insertion mutagenesis a c-myb gene knockdown (KD) line of mice. In the mice transgene was inserted 77-kb upstream of the c-myb gene and c-Myb expression was markedly decreased in megakaryocyte-erythrocyte lineage-restricted progenitors (MEPs) of the homozygous knockdown mutant mice (c-myb KD mice). The c-myb KD mice exhibited anemia, thrombocythemia, and splenomegaly and these abnormalities were reproducible in a co-culture assay of MEPs with OP9 cells, but abrogated by the retroviral expression of c-Myb in MEPs. To understand the transcriptional program that accompanies the decline of c-myb gene expression, we performed DNA microarray analysis with MEPs and identified 74 genes that are upregulated and 36 genes that are downregulated in the c-myb KD mice. Of these genes, expression levels 15 genes are actually changed significantly in bone marrow cells of the c-myb KD mice. These genes harbor c-Myb recognition elements in their regulatory regions. Especially, we found that the CD9 expression was upregulated in the c-myb KD mice. Reverse correlation of c-Myb expression with the CD9 gene expression was verified using a luciferase reporter assay and chromatin immunoprecipitation assay. Agonistic antibody of CD9 stimulated megakaryocytic colony formation. On the contrary, upon the bone marrow suppression with 5-fluorouracil recovery of platelet number was delayed in the CD9-null mice. Furthermore, proplatelet formation was impaired when we used CD9-null mouse megakaryocytes, and the size of proplatelets was smaller than those generated by wild-type megakaryocytes. These results thus demonstrate that c-Myb suppresses the CD9 expression in a steady-state condition, while in the stress megakaryopoiesis CD9 is derepressed and acts to induce the megakaryopoiesis. Elucidation of c-myb-based transcription network seems to be of important to understand the megakaryocytic differentiation.

Gene expression profiling related to the enhanced erythropoiesis in mouse bone marrow cells

2008 ◽  
Vol 104 (1) ◽  
pp. 295-303 ◽  
Author(s):  
Hee-Young Yang ◽  
Dong Kee Jeong ◽  
Seok-Ho Kim ◽  
Kyoung-Jin Chung ◽  
Eun-Jin Cho ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Bone Marrow Cells ◽  
Mouse Bone Marrow ◽  
Mouse Bone Marrow Cells ◽  
Marrow Cells

Erythropoietin Gene Expression in the Stromal Cell Increased by Silica to Induce Erythrocyte Differentiation

2013 ◽  
Vol 647 ◽  
pp. 494-498
Author(s):  
Wei Chung Liu ◽  
Chang Shu Tsai ◽  
Ya Yun Chen ◽  
Nien Tzu Keng
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Cells ◽  
Biological Effects ◽  
Interaction Mechanism ◽  
Silica Particles ◽  
Control Group ◽  
Stimulate Bone Marrow ◽  
Marrow Cells

Silica containing materials are often applied in bone tissue engineering, which may contact with bone marrow cells. However, the biological effects have not always been observed in studies of bone marrow cells exposed to silica. In this experiment, the relevant biological effects were evaluated. Bone marrow cells and stromal cells treated with silica particles (0.5-10 μm) were applied to investigate the possible interaction mechanism. HEL-92 cells were culture with the condition medium of stromal cells treated with or without silica particles. The erythrogenesis of bone marrow cells treated with silica particles was increased significantly. The expression level of glycophorin A the erythroid marker in HEL-92 cells treated by condition medium was higher than control group. The silica particles could also up-regulate the erythropoietin gene expression of stromal cells. The results indicate that bone marrow cells can be stimulated by silica particles to differentiate into erythrocytes. Our results suggest that silica particles can stimulate bone marrow cells to differentiate erythrocytes possibly via enhancing gene expression of erythropoietin.

scholarly journals Fibrin, Bone Marrow Cells and macrophages interactively modulate cardiomyoblast fate.

2022 ◽  
Author(s):  
Ines Borrego ◽  
Aurelien FROBERT ◽  
Guillaume AJALBERT ◽  
Jeremy VALENTIN ◽  
Cyrielle KALTENRIEDER ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Cardiac Function ◽  
Conditioned Medium ◽  
Bone Marrow Cells ◽  
Cardiac Repair ◽  
Cardiac Cell ◽  
Anti Inflammatory ◽  
Marrow Cells

Interactions between macrophages, cardiac cells and the extracellular matrix are crucial for cardiac repair following myocardial infarction (MI). The paracrine effects of cell-based treatments of MI might modulate these interactions and impact cardiac repair. The immunomodulatory capacity of the therapeutic cells is therefore of interest and could be modulated by the use of biomaterials. We first showed that bone marrow cells (BMC) associated with fibrin could treat MI. Then, we interrogated the influence of fibrin, as a biologically active scaffold, on the secretome of BMC and the impact of their association on macrophage fate and cardiomyoblast proliferation. Methods: In vivo, two weeks post-MI, rats were treated with epicardial implantation of BMC and fibrin or sham-operated. High-resolution echocardiography was performed to evaluate the heart function and structure changes after 4 weeeks. Histology and immunostaining were performed on harvested hearts. In vitro, BMC were first primed with fibrin. Second, non-polarized macrophages were differentiated toward either pro-inflammatory or anti-inflammatory phenotypes and stimulated with the conditioned medium of fibrin-primed BMC (F-BMC). Proteomic, cytokine levels quantification, and RT-PCR were performed. EdU incorporation and real-time cell analysis assessed cell proliferation. Results: The epicardial implantation of fibrin and BMC reduced the loss of cardiac function induced by MI, increased wall thickness and prevented the fibrotic scar expansion. After 4 and 12 weeks, the infarct content of CD68+ and CD206+ was similar in control and treated animals. In vitro, we showed that fibrin profoundly influenced the gene expression and the secretome of BMC, simultaneously upregulating both pro- and anti-inflammatory mediators. Furthermore, the conditioned medium from F-BMC significantly increased the proliferation of macrophages in a subsets dependent manner and modulated their gene expression and cytokines secretion. For instance, F-BMC significantly downregulated the expression of Nos2, Il6 and Ccl2/Mcp1 while Arg1, Tgfb and IL10 were upregulated. Interestingly, macrophages educated by F-BMC increased cardiomyoblast proliferation. In conclusion, our study provides evidence that BMC/fibrin-based treatment lowered the infarct extent and improved cardiac function. The macrophage content was unmodified when measured at a chronic stage. Nevertheless, acutely and in vitro, the F-BMC secretome promotes an anti-inflammatory response that stimulates cardiac cell growth. Finally, our study emphases the acute impact of F-BMC educated macrophages on cardiac cell fate.

scholarly journals Increased erythropoietin-receptor expression on CD34-positive bone marrow cells from patients with chronic myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 642-649 ◽  
Author(s):  
AW Wognum ◽  
G Krystal ◽  
CJ Eaves ◽  
AC Eaves ◽  
PM Lansdorp
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Erythropoietin Receptor ◽  
Receptor Expression ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Normal Individuals ◽  
Marrow Cells

Abstract Erythropoietin-receptor (EpR) expression on bone marrow cells from normal individuals and from patients with chronic myeloid leukemia (CML) was examined by multiparameter flow cytometry after stepwise amplified immunostaining with biotin-labeled Ep, streptavidin- conjugated R-phycoerythrin, and biotinylated monoclonal anti-R- phycoerythrin. This approach allowed the detection of EpR-positive cells in all bone marrow samples studied. Most of the EpR-positive cells in normal bone marrow were found to be CD45-dull, CD34-negative, transferrin-receptor-positive and glycophorin-A-intermediate to - positive. This phenotype is characteristic of relatively mature erythroid precursors, ie, colony-forming units-erythroid and erythroblasts recognizable by classic staining procedures. Approximately 5% of normal EpR-positive cells displayed an intermediate expression of CD45, suggesting that these represented precursors of the CD45-dull EpR-positive cells. Some EpR-positive cells in chronic myeloid leukemia (CML) bone marrow had a phenotype similar to the major EpR-positive phenotype in normal bone marrow, ie, CD34-negative and CD45-dull. However, there was a disproportionate increase in the relative number of EpR-positive/CD45-intermediate cells in CML bone marrow. Even more striking differences between normal individuals and CML patients were observed when EpR-expression on CD34-positive marrow cells was analyzed. Very few EpR-positive cells were found in the CD34- positive fraction of normal bone marrow, whereas a significant fraction of the CD34-positive marrow cells from five of five CML patients expressed readily detectable EpR. These findings suggest that control of EpR expression is perturbed in the neoplastic clone of cells present in patients with CML. This may be related to the inadequate output of mature red blood cells typical of CML patients and may also be part of a more generalized perturbation in expression and/or functional integrity of other growth factor receptors on CML cells.

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