Epigenetic Silencing of Bcl-2, C/Ebpa and p14ARF by the AML1/ETO Oncoprotein Contributing to Growth Arrest and Differentiation Blockage

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3617-3617
Author(s):  
Wen-yue Zhuang ◽  
Zi-Xing Chen
Keyword(s):  
Transcription Factor ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Histone H3 ◽  
Growth Arrest ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Granulocytic Differentiation ◽  
Factor C ◽  
Acute Myeloid

Abstract Abstract 3617 The t(8; 21) is one of the most frequent chromosomal translocations associated with acute leukemia. The AML1(RUNX1)-ETO(MTG8) fusion transcription factor generated by the t (8; 21) translocation is believed to deregulate the expression of genes that are crucial for normal differentiation and proliferation of hematopoietic progenitors, resulting in acute myelogenous leukemia by recruiting co-repressor complexes to DNA. To investigate the role of AML1-ETO in leukemogenesis, we transfected the cloned AML1-ETO cDNA with plasmid and expressed the AML1-ETO protein in U937 myelomonocytic leukemia cells. Interestingly, we found dichotomous phenomena in these transfected leukemic cells, i.e. growth arrest versus differentiation block (detailed data?). The AML1-ETO transfected U937cells were growing significantly slower than that of empty vector-transfected cells and nontransfected cells (P<0.01). As the surface markers for myeloid differentiation, the expression of CD11b and CD14 measured by flow cytometry demonstrated that the percentage of CD11b+ cell was 4.1%-7.0% in U937-A/E1-4 cells, which was significantly lower(P<0.01) than those in U937-Mock cells (11.4%) and U937-WT cells (11.0%). Moreover, the expression of CD14 antigen was decreased by 1.5–2-fold as compared with the control cells. By focusing on the anti-apoptotic gene (Bcl-2), a key transcription factor (C/EBPA) which regulates granulocytic differentiation and a tumor suppressor gene (p14ARF), we found that AML1-ETO- expressing cell subclones displayed low levels of these three genes in comparison with the non-transfected U937 (P<0.001). In primary bone marrow cells of acute myeloid leukemia containing t(8;21)/AML1-ETO, levels of Bcl-2, C/EBPA and p14ARF mRNA were markedly lower (P<0.001) when compared with other acute myeloid leukemias lacking this translocation (n=10). Chromatin immunoprecipitation assays (ChIP) demonstrated that Bcl-2, C/EBPA and p14ARF were among the direct transcriptional regulating targets of AML1-ETO. The universal binding of AML1-ETO to genomic DNA resulted in MeCP2 recruitment (P<0.01), reduction of histone H3 (P<0.0 1) or histone H4(P<0.01) acetylation and increased tri-methylation on histone H3 lysine 9 (P<0.01)as well as histone H3 lysine 27 (P<0.01), indicating that AML1-ETO induced heterochromatic silencing of Bcl-2, C/EBPA and p14ARF. These results suggested that the aberrant transcription factor AML1-ETO epigenetically silences the function of Bcl-2, C/EBPA and p14ARF gene by inducing repressed chromatin configurations at their promoters through histone modification. Considering that apoptosis-enhancing effect of AML1-ETO would not be favorable to the leukemogenesis, it must be compensated by some other effects to permit its leukemogenic potential. Disclosures: No relevant conflicts of interest to declare.

Myeloid Transcription Factor C/EBPɛ Is Involved in the Positive Regulation of Lactoferrin Gene Expression in Neutrophils

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3141-3150 ◽  
Author(s):  
Walter Verbeek ◽  
Julie Lekstrom-Himes ◽  
Dorothy J. Park ◽  
Pham My-Chan Dang ◽  
Peter T. Vuong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Bone Marrow Cells ◽  
Granulocytic Differentiation ◽  
Direct Role ◽  
Gram Negative ◽  
Protein Levels ◽  
Factor C ◽  
Marrow Cells

Abstract Targeted mutation of the myeloid transcription factor C/EBPɛ in mice results in gram-negative septic death at 3 to 5 months of age. This study defines the underlying molecular defects in their terminal granulocytic differentiation. The mRNA for the precursor protein of the cathelin-related antimicrobial peptides was almost completely absent in the bone marrow cells of C/EBPɛ−/− mice. This finding may help explain their susceptibility to gram-negative sepsis, because both are bacteriocidal peptides with potent activity against gram-negative bacteria. Superoxide production was found to be reduced in both granulocytes and monocytes of C/EBPɛ−/− mice. While gp91 phox protein levels were normal, p47phox protein levels were considerably reduced in C/EBPɛ −/− granulocytes/monocytes, possibly limiting the assembly of the NADPH oxidase. In addition, expression of mRNA of the secondary and tertiary granule proteins, lactoferrin and gelatinase, were not detected, and levels of neutrophil collagenase mRNA were reduced in bone marrow cells of the knock-out mice. The murine lactoferrin promoter has a putative C/EBP site close to the transcription start site. C/EBPɛ bound to this site in electromobility shift assay studies and mutation of this site abrogated binding to it. A mutation in the C/EBP site reduced the activity of the promoter by 35%. Furthermore, overexpression of C/EBPɛ in U937 cells increased the activity of the wild-type lactoferrin promoter by 3-fold. In summary, our data implicate C/EBPɛ as a critical factor of host antimicrobial defense and suggests that it has a direct role as a positive regulator of expression of lactoferrin in vivo.

C/EBPα-Induced MicroRNA 30c Inactivates Notch1 During Granulopoiesis and Is Downregulated In Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2368-2368
Author(s):  
Christiane Katzerke ◽  
Vikas Madan ◽  
Dennis Gerloff ◽  
Daniela Braeuer-Hartmann ◽  
Jens-Uwe Hartmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Mrna Level ◽  
Granulocytic Differentiation ◽  
Hematopoietic Stem ◽  
Knock Out ◽  
Human Cd34 ◽  
Acute Myeloid

Abstract Abstract 2368 The transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPα) is crucial for normal granulopoiesis and frequently disrupted in acute myeloid leukemia (AML). Loss of expression or function of C/EBPα leads to a block of myeloid differentiation. MicroRNAs inhibiting translation of mRNA into protein were identified as critical players in stem cell development. We and others have already shown that C/EBPα exerts its effects by regulating microRNAs such as miR-223 and miR-34a. In a global microRNA-array screen we found miR-30c as a novel target of C/EBPα during granulocytic differentiation. Wild-type C/EBPα-p42 upregulates miR-30c expression, whereas the C/EBPα-p30 mutant, found in AML, does not. Furthermore, G-CSF upregulates miR-30c expression during granulocytic differentiation of primary human CD34-positive progenitor cells. C/EBPα induces miR-30c and downregulates Notch1, a putative target of miR-30c, on protein, but not mRNA level. A block of miR-30c by LNAs prevents C/EBPα–induced downregulation of Notch1 protein expression. miR-30c is a tumor suppressor and downregulated in various subtypes of AML. In mice, miR-30c shows a high expression in LSK (including hematopoietic stem cells), GMP (granulocytic monocytic precursors) and granulocytes. An induced knock-out of C/EBPα in mice leads to a significantly downregulation of miR-30c expression in bone marrow cells. Our data indicates that C/EBPα-induced miR-30c inactivates Notch1 during granulopoiesis and is downregulated in AML. These data reveal the importance of deregulated microRNA expression in leukemia and may provide novel biomarkers and therapeutic targets in AML. Disclosures: No relevant conflicts of interest to declare.

5-Azacytidine and G-CSF Derepressed Chromatin Structure of PU.1 and Its Targets Cebpa and Cbfb In Myelodysplastic Syndrome (MDS)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 124-124
Author(s):  
Tomas Stopka ◽  
Pavel Burda ◽  
Petra Basova ◽  
Karin Vargova ◽  
Nikola Curik ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Myelodysplastic Syndrome ◽  
Cell Lines ◽  
Chromatin Structure ◽  
Dna Methyltransferase ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Epigenetic Therapy ◽  
Number Of Patients

Abstract Abstract 124 The myelodysplastic syndrome (MDS) represents a heterogeneous disorder characterized by ineffective hematopoiesis and evolution to acute myelogenous leukemia that is strikingly refractory to current therapeutic approaches. Novel epigenetic drugs including DNA-methyltransferase inhibitor 5-Azacitidine (5-AZA, Vidaza) are currently considered to improve clinical response in patients with MDS. MDS is characterized by abnormal differentiation and blocked maturation responsive to 5-AZA, therefore we studied major regulator of hematopoietic differentiation, transcription factor PU.1 as a candidate target of the epigenetic therapy. Transcription factor PU.1 represents very important myelo-lymphoid regulator of differentiation. PU.1 expression is regulated by Upstream Regulatory Element (URE) and its deletion in mouse caused downregulation of PU.1 leading to acute leukemia (Rosenbauer 2004). Our laboratory recently demonstrated that PU.1 in murine acute leukemic cells binds and promotes derepression of CCAAT/enhancer binding protein (C/EBP) alpha (Cebpa) and Core-binding factor, beta subunit (Cbfb) (Burda 2009) that encode two key hematopoietic transcription factors involved in myeloid differentiation. Furthermore, transcriptional regulation through PU.1 binding sites of Cebpa and Cbfb loci involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3 lysine K9. Others reported that Cebpa expression is augmented by G-CSF (Dahl 2003). To determine if 5-AZA regulates PU.1 and its targets we determined their expression and chromatin structure following the 5-AZA treatment in MDS patient-derived blasts and in cell lines derived from MDS (MOLM-13, OCI-M2, SKM-1) and AML (K562). Our data provide evidence that in the chosen cell lines and in so far limited number of patients-derived cells (N=4) the gene expression of PU.1 and its direct targets Cebpa and Cbfb is stimulated by 5-AZA and this effect is further enhanced by G-CSF. Furthermore, marks of activated chromatin structure including histone H3K9 hyperacetylation and H3K4 hypermethylation are increased at the URE of the PU.1 gene again documenting its transcriptional activation. Conversely, levels of H3K9 methylation at URE are significantly reduced upon 5-AZA treatment documenting 5-AZA stimulates loss of repressive chromatin structure near PU.1 gene. These observations are currently compared with responsiveness of the patients to 5-AZA in vivo and expanded to larger set of patients. Our data collectively supports importance of the chromatin structure upstream of PU.1 gene and of its direct targets Cebpa and Cbfb in patients with MDS that may add to better understanding of effectiveness of epigenetic therapy in MDS. (Grants # IGA 10310-3, MSMT 2B06077, SVV-2010-254260507, MPO FR-TI2/509, GAUK 251135 82210). Disclosures: No relevant conflicts of interest to declare.

Myeloid Transcription Factor C/EBPɛ Is Involved in the Positive Regulation of Lactoferrin Gene Expression in Neutrophils

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3141-3150 ◽  
Author(s):  
Walter Verbeek ◽  
Julie Lekstrom-Himes ◽  
Dorothy J. Park ◽  
Pham My-Chan Dang ◽  
Peter T. Vuong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Bone Marrow Cells ◽  
Granulocytic Differentiation ◽  
Direct Role ◽  
Gram Negative ◽  
Protein Levels ◽  
Factor C ◽  
Marrow Cells

Targeted mutation of the myeloid transcription factor C/EBPɛ in mice results in gram-negative septic death at 3 to 5 months of age. This study defines the underlying molecular defects in their terminal granulocytic differentiation. The mRNA for the precursor protein of the cathelin-related antimicrobial peptides was almost completely absent in the bone marrow cells of C/EBPɛ−/− mice. This finding may help explain their susceptibility to gram-negative sepsis, because both are bacteriocidal peptides with potent activity against gram-negative bacteria. Superoxide production was found to be reduced in both granulocytes and monocytes of C/EBPɛ−/− mice. While gp91 phox protein levels were normal, p47phox protein levels were considerably reduced in C/EBPɛ −/− granulocytes/monocytes, possibly limiting the assembly of the NADPH oxidase. In addition, expression of mRNA of the secondary and tertiary granule proteins, lactoferrin and gelatinase, were not detected, and levels of neutrophil collagenase mRNA were reduced in bone marrow cells of the knock-out mice. The murine lactoferrin promoter has a putative C/EBP site close to the transcription start site. C/EBPɛ bound to this site in electromobility shift assay studies and mutation of this site abrogated binding to it. A mutation in the C/EBP site reduced the activity of the promoter by 35%. Furthermore, overexpression of C/EBPɛ in U937 cells increased the activity of the wild-type lactoferrin promoter by 3-fold. In summary, our data implicate C/EBPɛ as a critical factor of host antimicrobial defense and suggests that it has a direct role as a positive regulator of expression of lactoferrin in vivo.

Oridonin-Generated Cleavage Fragment of AML1-ETO Inhibits Its Oligomerization and Oncogenic Function Leading to Differentiation and Apoptosis of Leukemic Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1051-1051
Author(s):  
Chuanfeng Wu ◽  
Tao Zhen ◽  
Guangbiao Zhou ◽  
Ping Liu ◽  
Zhu Chen ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Dominant Negative ◽  
Leukemic Cells ◽  
Granulocytic Differentiation ◽  
Regulatory Pathways ◽  
Cleavage Fragment

Abstract Abstract 1051 Poster Board I-73 Oligomerization through the NHR2 domain is essential for AML1-ETO's inhibition of granulocytic differentiation and enhanced clonogenic potential of primary bone marrow cells. We show here that Oridonin interferes with AML1-ETO oligomerization through its cleavage fragment DAML1-ETO, which consists of the amino acids (aa) 188-752 of the parental oncoprotein or aa 40-604s of the wild-type ETO. DAML1-ETO interacts with the parental AML1-ETO through NHR2 and exerts dominant negative effects on AML1-ETO with regard to DNA binding, transregulatory activity on target genes and regulation of leukemic cell survival, differentiation and proliferation both in vitro and in vivo. Moreover, Oridonin can activate retinoic acid and cAMP/PKA pathways, and potentiate differentiation induced by all-trans retinoic acid (ATRA) and G-CSF. Consistently, combined use of Oridonin, ATRA and G-CSF significantly prolongs lifespan of t (8;21) leukemic mice and, interestingly, we find that this treatment targets the Lin-/Sca-1+/C-KIT+ and Lin-/Sca-1-/C-KIT+ leukemia initiating cells. These data suggest that Oridonin, and potentially other small molecules, can inhibit AML1-ETO oligomerization and leukemogenic function, thus providing a targeted therapy that activates key regulatory pathways for myelomonocytic cell differentiation and apoptosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Ian Edward Gentle ◽  
Isabel Moelter ◽  
Mohamed Tarek Badr ◽  
Konstanze Döhner ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Wild Type ◽  
Elevated Expression ◽  
Factor C ◽  
Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

scholarly journals Downregulation of c-Jun Expression by Transcription Factor C/EBPα Is Critical for Granulocytic Lineage Commitment

2002 ◽  
Vol 22 (24) ◽  
pp. 8681-8694 ◽  
Author(s):  
Janki Rangatia ◽  
Rajani Kanth Vangala ◽  
Nicolai Treiber ◽  
Pu Zhang ◽  
Hanna Radomska ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Knockout Mouse ◽  
Leucine Zipper ◽  
Fetal Liver ◽  
Mrna Level ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Conditional Expression ◽  
Factor C ◽  
Transcription Factor Complex

ABSTRACT The transcription factor C/EBPα is crucial for the differentiation of granulocytes. Conditional expression of C/EBPα triggers neutrophilic differentiation, and C/EBPα can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBPα knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBPα knockout mouse fetal liver was observed. c-Jun, a component of the AP-1 transcription factor complex and a coactivator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPα downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBPα expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBPα. C/EBPα and c-Jun interact through their leucine zipper domains, and this interaction prevents c-Jun from binding to DNA. This results in downregulation of c-Jun's capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-Jun prevents C/EBPα-induced granulocytic differentiation. Thus, we propose a model in which C/EBPα needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.

scholarly journals Processing enzymes acting on carbohydrate moiety of lysosomal hydrolases in leukemic cells: elevated activity of N-acetylglucosamine- 1-phosphotransferase

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1957-1962 ◽  
Author(s):  
Y Uehara ◽  
S Gasa ◽  
A Makita ◽  
M Oh-hira ◽  
K Sakurada ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Activity Level ◽  
Carbohydrate Moiety ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Variant Form ◽  
Lysosomal Hydrolases ◽  
Processing Enzymes ◽  
Processing Enzyme ◽  
Arylsulfatase B

Abstract We previously demonstrated that an acidic variant form of lysosomal arylsulfatase B accumulated in chronic myelogenous leukemia (CML) cells was highly phosphorylated at its carbohydrate moiety (Uehara Y, et al, Cancer Res 43:5618, 1983). Since lysosomal hydrolases including the sulfatase underwent the posttranslational phosphorylation processing at the carbohydrate moiety, we investigated two enzymes acting on the processing in peripheral leukocytes from leukemia patients. The activity level of the first enzyme in the processing, an N- acetylglucosamine-1-phosphotransferase to form phosphodiester at the carbohydrates, was significantly higher in CML cells than in normal control. The transferase level in CML cells was also higher compared with that in normal bone marrow cells, which include myeloid progenitor cells. However, the activity of the second processing enzyme, a phosphodiester glycosidase that converts a phosphodiester to a phosphomonoester, showed no consistent change in CML cells. Thus, increment of the sulfatase variant containing phosphomonoesters and diesters in CML cells is most probably associated with elevated activities of the phosphotransferase. In two cases of CML in blastic crisis and a case of acute myelogenous leukemia (AML), activity of the processing enzyme was considerably decreased concomitant with reduction of peripheral blastic cells by chemotherapy.

scholarly journals Anti-MY9-blocked-ricin: an immunotoxin for selective targeting of acute myeloid leukemia cells

Blood ◽  
1991 ◽  
Vol 77 (11) ◽  
pp. 2404-2412 ◽  
Author(s):  
DC Roy ◽  
JD Griffin ◽  
M Belvin ◽  
WA Blattler ◽  
JM Lambert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Leukemic Cells ◽  
Short Exposure ◽  
Continuous Exposure ◽  
Dependent Manner ◽  
Acute Myeloid

Abstract The use of immunotoxins (IT) to selectively destroy acute myeloid leukemia (AML) cells in vivo or in vitro is complicated by both the antigenic similarity of AML cells to normal progenitor cells and the difficulty of producing a sufficiently toxic conjugate. The monoclonal antibody (MoAb) anti-MY9 is potentially ideal for selective recognition of AML cells because it reacts with an antigen (CD33) found on clonogenic AML cells from greater than 80% of cases and does not react with normal pluripotent stem cells. In this study, we describe an immunotoxin that is selectively active against CD33+ AML cells: Anti- MY9-blocked-Ricin (Anti-MY9-bR), comprised of anti-MY9 conjugated to a modified whole ricin that has its nonspecific binding eliminated by chemical blockage of the galactose binding domains of the B-chain. A limiting dilution assay was used to measure elimination of HL-60 leukemic cells from a 20-fold excess of normal bone marrow cells. Depletion of CD33+ HL-60 cells was found to be dependent on the concentration of Anti-MY9-bR and on the duration of incubation with IT at 37 degrees C. More than 4 logs of these leukemic cells were specifically depleted following short exposure to high concentrations (10(-8) mol/L) of Anti-MY9-bR. Incubation with much lower concentrations of Anti-MY9-bR (10(-10) mol/L), as compatible with in vivo administration, resulted in 2 logs of depletion of HL-60 cells, but 48 to 72 hours of continuous exposure were required. Anti-MY9-bR was also shown to be toxic to primary AML cells, with depletion of greater than 2 logs of clonogenic cells following incubation with Anti- MY9-bR 10(-8) mol/L at 37 degrees C for 5 hours. Activity of Anti-MY9- bR could be blocked by unconjugated Anti-MY9 but not by galactose. As expected, Anti-MY9-bR was toxic to normal colony-forming unit granulocyte-monocyte (CFU-GM), which expresses CD33, in a concentration- and time-dependent manner, and also to burst-forming unit-erythroid and CFU-granulocyte, erythroid, monocyte, megakaryocyte, although to a lesser extent. When compared with anti-MY9 and complement (C′), Anti- MY9-bR could be used in conditions that provided more effective depletion of AML cells with substantially less depletion of normal CFU- GM. Therefore, Anti-MY9-bR may have clinical utility for in vitro purging of AML cells from autologous marrow when used at high IT concentrations for short incubation periods. Much lower concentrations of Anti-MY9-bR that can be maintained for longer periods may be useful for elimination of AML cells in vivo.

scholarly journals Effect of Erythropoietin on RNA Synthesis by Normal and Leukemic Bone Marrow and Spleen Cell Suspensions In Vitro

Blood ◽  
1974 ◽  
Vol 44 (4) ◽  
pp. 535-542 ◽  
Author(s):  
Evelyn E. Handler ◽  
Naomi Mendelsohn ◽  
Eugene S. Handler
Keyword(s):  
Bone Marrow ◽  
Rna Synthesis ◽  
Bone Marrow Cells ◽  
Marrow Cell ◽  
Cell Suspensions ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Spleen Cells ◽  
Normal Bone Marrow Cell

Abstract Erythropoietin (EPO) induced a 42% increase in 3H-uridine incorporation into RNA after a 5-hr culture of normal bone marrow cell suspensions. Bone marrow cells obtained from rats 3-5 days after the initiation of a myelogenous leukemia exhibited a decreased responsivity to EPO. At this time incorporation of the isotope into RNA in the presence of EPO was approximately 50% of controls. Rats rendered leukemic 8-10 days prior to culture showed no bone marrow response to EPO even in those instances where leukemic cells comprised a relatively small percentage of the marrow compartment. EPO had little or no effect on RNA synthesis by spleen cells obtained from normal and leukemic rats. This was noted even in those leukemic spleens in which erythropoiesis was observed. The data suggest that the anemia associated with myelogenous leukemia may, in part, be due to a loss of EPO-responsive cells and/or a loss of sensitivity of these elements to normal humoral control.

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