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Daniel E. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Src family kinase gene targets during Myeloid Differentiation: identification of the EGR-1 gene as a direct target.
Leukemia, 2009Co-Authors: J.e. Jones, Patricia Kropf, R Duan, L. Wang, Daniel E. JohnsonAbstract:Src family kinase gene targets during Myeloid Differentiation: identification of the EGR-1 gene as a direct target
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Src family kinase gene targets during Myeloid Differentiation: identification of the EGR-1 gene as a direct target.
Leukemia, 2009Co-Authors: J.e. Jones, Patricia Kropf, R Duan, L. Wang, Daniel E. JohnsonAbstract:Src family kinase gene targets during Myeloid Differentiation: identification of the EGR-1 gene as a direct target
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Inhibition of Src family kinases enhances retinoic acid induced gene expression and Myeloid Differentiation.
Molecular cancer therapeutics, 2007Co-Authors: Michelle B. Miranda, Robert L Redner, Daniel E. JohnsonAbstract:Treatment of acute promyelocytic leukemia with retinoic acid (RA) results in Differentiation of the leukemic cells and clinical remission. However, the cellular factors that regulate RA-induced Myeloid Differentiation are largely unknown, and other forms of acute myelogenous leukemia (AML) do not respond to this Differentiation therapy. A greater understanding of the molecules that positively or negatively regulate RA-induced Differentiation should facilitate the development of more effective Differentiation therapies. In this study, we investigated the potential role of Src family kinases (SFK) in the regulation of RA-induced gene expression and Myeloid Differentiation. We report that inhibition of SFKs markedly enhanced RA-induced Differentiation in Myeloid cell lines and primary AML cells, as assessed by flow-cytometric analysis of cell surface markers, morphologic analysis, and nitroblue tetrazolium reduction. In addition, inhibition of SFKs enhanced expression from retinoic acid receptor (RAR) target genes encoding CCAAT/enhancer binding protein epsilon (C/EBPepsilon), PU.1, intercellular adhesion molecule-1 (ICAM-1), and cathepsin D. Moreover, a constitutively active Src inhibited RAR-dependent transcription, whereas a kinase-dead Src exerted little effect. These studies provide the first demonstration that SFKs act to negatively regulate RA-induced gene expression and Myeloid Differentiation and suggest that the combination of SFK inhibition and RA treatment may be therapeutically beneficial in AML.
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Inhibition of Src family kinases enhances retinoic acid-induced gene expression and Myeloid Differentiation
Molecular Cancer Therapeutics, 2007Co-Authors: Michelle B. Miranda, Robert L Redner, Daniel E. JohnsonAbstract:Treatment of acute promyelocytic leukemia with retinoic acid (RA) results in Differentiation of the leukemic cells and clinical remission. However, the cellular factors that regulate RA-induced Myeloid Differentiation are largely unknown, and other forms of acute myelogenous leukemia (AML) do not respond to this Differentiation therapy. A greater understanding of the molecules that positively or negatively regulate RA-induced Differentiation should facilitate the development of more effective Differentiation therapies. In this study, we investigated the potential role of Src family kinases (SFK) in the regulation of RA-induced gene expression and Myeloid Differentiation. We report that inhibition of SFKs markedly enhanced RA-induced Differentiation in Myeloid cell lines and primary AML cells, as assessed by flow-cytometric analysis of cell surface markers, morphologic analysis, and nitroblue tetrazolium reduction. In addition, inhibition of SFKs enhanced expression from retinoic acid receptor (RAR) target genes encoding CCAAT/enhancer binding protein e (C/EBPe), PU.1, intercellular adhesion molecule-1 (ICAM-1), and cathepsin D. Moreover, a constitutively active Src inhibited RAR-dependent transcription, whereas a kinase-dead Src exerted little effect. These studies provide the first demonstration that SFKs act to negatively regulate RA-induced gene expression and Myeloid Differentiation and suggest that the combination of SFK inhibition and RA treatment may be therapeutically beneficial in AML. [Mol Cancer Ther 2007;6(12):3081–90]
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Src family kinases and the MEK/ERK pathway in the regulation of Myeloid Differentiation and Myeloid leukemogenesis
Advances in enzyme regulation, 2007Co-Authors: Daniel E. JohnsonAbstract:The production of mature monocytes/macrophages and granulocytes via Myeloid Differentiation is a central component of the host defense mechanism against invading microorganisms. However, in Myeloid leukemias genetic changes lead to blockade of Myeloid Differentiation. When this happens, immune responses can become severely impaired and the accumulation of proliferative blasts causes bone marrow crowding and onset of symptomatic leukemia. There is considerable hope that molecular targeting of specific signaling pathways and proteins will prove to be a viable strategy for restoring Differentiation potential in Myeloid leukemias. Indeed, in acute promyelocytic leukemia, treatment with ATRA can overcome the Differentiation blockade and is an effective curative approach. To devise strategies and reagents that can be used to induce Differentiation in other Myeloid leukemias, it is important to gain an understanding of the molecular pathways that drive the normal Differentiation process. Emerging evidence implicates both Src family kinases and the MEK/ERK pathway in regulating Myeloid Differentiation. It is interesting that Src family kinases appear to be negative regulators of myelopoiesis, while the MEK/ERK pathway is an important positive regulator of both monocytic and granulocytic Differentiation. This suggests that pharmacologic inhibitors of SFKs may be of value in restoring or enhancing Myeloid Differentiation. In this regard, the SFK inhibitor dasatinib has recently been approved by the FDA for use in imatinib-resistant CML. Evaluation of dasatinib, alone or in combination with Differentiation inducers, in the treatment of Differentiation-defective AML seems warranted. The important role that the MEK/ERK pathway plays in promoting Myeloid Differentiation appears to conflict with observations that the MEK/ERK pathway is hyperactivated or overexpressed in a majority of primary AMLs. Moreover, pharmacologic inhibition of the MEK/ERK pathway in AML results in the induction of apoptosis, indicating that MEK/ERK activation is important for the survival of AML cells. Collectively, these data suggest that the MEK/ERK pathway may play more than one role in Myeloid lineage cells, depending on the cellular context. In normal Myeloid cells, activation of the MEK/ERK pathway is important for promoting Differentiation. However, when Differentiation becomes blocked, as is the case in most AMLs, MEK/ERK activation can no longer drive Differentiation, and instead begins to support cellular survival or proliferation. Thus, therapeutic strategies aimed at provoking Myeloid Differentiation in AML by stimulating the MEK/ERK pathway are unlikely to be successful unless the Differentiation blockade is simultaneously relieved.
Barbara Hoffman - One of the best experts on this subject based on the ideXlab platform.
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The c‐myc apoptotic response is not intrinsic to blocking terminal Myeloid Differentiation
Journal of cellular physiology, 2008Co-Authors: Santo A. D’angelo, Dan A. Liebermann, Barbara HoffmanAbstract:It has previously been shown that deregulated c-myc blocks terminal Myeloid Differentiation and prematurely recruits both the Type I and II CD95/Fas apoptotic pathways, promoting an incompletely penetrant apoptotic response. In this work it is shown that deregulated expression of either mycER or mycER™ variants also blocked terminal Myeloid Differentiation but failed to induce the apoptotic response, demonstrating that c-myc can block Differentiation independent of the apoptotic response. The failure of the mycER™ transgene to cause the apoptotic response is associated with reduced levels of RIP1 expression, increased Mcl-1 expression and activation of both NF-kB and Akt. In addition, deregulating expression of RIP1 in M1mycER™ cells restored the apoptotic response. Thus altering c-Myc or its downstream effectors can influence the balance between apoptosis and survival, and ultimately the oncogenic potential of the c-myc oncogene. This knowledge can be exploited to manipulate the downstream effectors, such as RIP1, to promote apoptosis and drive the death of cancer cells. J. Cell. Physiol. 216: 120–127, 2008. © 2008 Wiley-Liss, Inc.
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Egr-1 abrogates the E2F-1 block in terminal Myeloid Differentiation and suppresses leukemia.
Oncogene, 2007Co-Authors: John D. Gibbs, Dan A. Liebermann, Barbara HoffmanAbstract:Deregulated growth and blocks in Differentiation collaborate in the multistage process of leukemogenesis. Previously, we have shown that ectopic expression of the zinc finger transcription factor Egr-1 in M1 myeloblastic leukemia cells promotes terminal Differentiation with interleukin-6 (IL-6). In addition, we have shown that deregulated expression of the oncogene E2F-1 blocks the Myeloid terminal Differentiation program, resulting in proliferation of immature cells in the presence of IL-6. Here it is shown that the positive regulator of Differentiation Egr-1 abrogates the E2F-1-driven block in Myeloid terminal Differentiation. The M1E2F-1/Egr-1 cells underwent G0/G1 arrest and functional macrophage maturation following treatment with IL-6. Furthermore, Egr-1 diminished the aggressiveness of M1E2F-1 leukemias and abrogated the leukemic potential of IL-6-treated M1E2F-1 cells. Previously, we reported that Egr-1 abrogated the block in terminal Myeloid Differentiation imparted by deregulated c-myc, which blocks Differentiation at a later stage than E2F-1, resulting in cells that have the characteristics of functionally mature macrophages that did not undergo G0/G1 arrest. Taken together, this work extends and highlights the tumor suppressor role of Egr-1, with Egr-1 behaving as a tumor suppressor against two oncogenes, each blocking Myeloid Differentiation by a different mechanism. These findings suggest that Egr-1 and/or Egr-1 target genes may be useful tools to treat or suppress oncogene-driven hematological malignancies.
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Terminal Myeloid Differentiation is Uncoupled from Cell Cycle Arrest
Cell cycle (Georgetown Tex.), 2007Co-Authors: John D. Gibbs, Dan A. Liebermann, Barbara HoffmanAbstract:It has been assumed that terminal Myeloid Differentiation and cell cycle arrest are coupled processes, and that prohibiting cell cycle arrest blocks Differentiation. Previously we have shown that, using the murine M1 Myeloid leukemic cell line, deregulated expression of the proto-oncogene c-myc results in cells that cannot be induced to undergo terminal Differentiation and continued to proliferate. It has also been shown that ectopic expression of Egr-1 abrogated the c-Myc block in terminal Myeloid Differentiation, yet there was no accumulation of cells in the G0/G1 phase of the cell cycle. In this study we conclusively demonstrate that M1Myc/Egr-1 cells terminally differentiate while still actively cycling and synthesizing DNA, concluding that the terminal Myeloid Differentiation program is uncoupled from growth arrest. How deregulated expression/activation of proto-oncogenes that promote cell cycle progression interferes with Differentiation and how Differentiation is regulated independently of cell cyc...
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Fos modulates Myeloid cell survival and Differentiation and partially abrogates the c-Myc block in terminal Myeloid Differentiation.
Blood, 2004Co-Authors: Marianna Shafarenko, Dan A. Liebermann, Arshad Amanullah, Bernard Gregory, Barbara HoffmanAbstract:Previously, we have shown that Fos/Jun transcription factor complexes function as positive modulators of Myeloid Differentiation. Fos, which is stably induced during normal Myeloid Differentiation, is not induced upon Differentiation of M1 myeloblastic leukemia cells. Establishing M1 cells that express a β-estradiol-conditional FosER chimera, we show that in the absence of the Differentiation inducer interleukin-6 (IL-6), Fos expression in M1 myeloblasts promoted apoptotic cell death, entailing cytochrome c release and caspase-9 activation. In contrast, in the presence of IL-6, Fos-mediated apoptosis was abrogated, and Fos promoted terminal Differentiation, increasing the sensitivity of M1 cells to be induced for Differentiation by IL-6. Fos-mediated apoptosis was accelerated by deregulated c-Myc. Furthermore, restoring Fos expression in M1 partially abrogated the block imparted by deregulated c-Myc on the Myeloid Differentiation program, increased the sensitivity of the cells to be induced for Differentiation, and curtailed their leukemic phenotype. These data provide evidence that Fos/Jun transcription factor complexes play a role in modulating both Myeloid cell survival and Differentiation and suggest that genetic lesions that alter Fos expression may cooperate with deregulated c-Myc in leukemogenesis. (Blood. 2004;103:4259-4267)
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Myeloid Differentiation (MyD) primary response genes in hematopoiesis.
Blood cells molecules & diseases, 2003Co-Authors: Dan A. Liebermann, Barbara HoffmanAbstract:Myeloid Differentiation (MyD) primary response and growth arrest DNA-damage (Gadd) genes comprise a set of overlapping genes, including known (IRF-1, EGR-1, Jun) and novel (MyD88, Gadd45a MyD118/Gadd45b, GADD45g, MyD116/Gadd34) genes, that have been cloned by virtue of being coordinately induced upon the onset of terminal Myeloid Differentiation. This review delineates the role MyD genes were found to play in blood cell development, where they function as positive regulators of terminal Differentiation, lineage specific blood cell development, and control of blood cell homeostasis, including growth inhibition and apoptosis.
J.e. Jones - One of the best experts on this subject based on the ideXlab platform.
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Src family kinase gene targets during Myeloid Differentiation: identification of the EGR-1 gene as a direct target.
Leukemia, 2009Co-Authors: J.e. Jones, Patricia Kropf, R Duan, L. Wang, Daniel E. JohnsonAbstract:Src family kinase gene targets during Myeloid Differentiation: identification of the EGR-1 gene as a direct target
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Src family kinase gene targets during Myeloid Differentiation: identification of the EGR-1 gene as a direct target.
Leukemia, 2009Co-Authors: J.e. Jones, Patricia Kropf, R Duan, L. Wang, Daniel E. JohnsonAbstract:Src family kinase gene targets during Myeloid Differentiation: identification of the EGR-1 gene as a direct target
Robert L Redner - One of the best experts on this subject based on the ideXlab platform.
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NPM–RAR, not the RAR–NPM reciprocal t(5;17)(q35;q21) acute promyelocytic leukemia fusion protein, inhibits Myeloid Differentiation
Leukemia & lymphoma, 2013Co-Authors: Sheri L. Pollock, Elizabeth A. Rush, Robert L RednerAbstract:The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the nucleophosmin (NPM) gene at 5q35 with the retinoic acid receptor alpha (RARA) at 17q12-22. We have previously shown that leukemic cells express both NPM-RAR and RAR- NPM reciprocal translocation products. In this study we investigated the potential role of both proteins in modulating Myeloid Differentiation. Expression of NPM-RAR inhibited vitamin D3/transforming growth factor β (TGFβ)-mediated Differentiation of U937 cells by more than 50%. In contrast, RAR-NPM expression did not alter vitamin D3/TGFβ-induced Differentiation of U937 clones. These results indicate that NPM-RAR, not RAR-NPM, is the prime mediator of Myeloid Differentiation arrest in t(5;17) APL.
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Inhibition of Src family kinases enhances retinoic acid induced gene expression and Myeloid Differentiation.
Molecular cancer therapeutics, 2007Co-Authors: Michelle B. Miranda, Robert L Redner, Daniel E. JohnsonAbstract:Treatment of acute promyelocytic leukemia with retinoic acid (RA) results in Differentiation of the leukemic cells and clinical remission. However, the cellular factors that regulate RA-induced Myeloid Differentiation are largely unknown, and other forms of acute myelogenous leukemia (AML) do not respond to this Differentiation therapy. A greater understanding of the molecules that positively or negatively regulate RA-induced Differentiation should facilitate the development of more effective Differentiation therapies. In this study, we investigated the potential role of Src family kinases (SFK) in the regulation of RA-induced gene expression and Myeloid Differentiation. We report that inhibition of SFKs markedly enhanced RA-induced Differentiation in Myeloid cell lines and primary AML cells, as assessed by flow-cytometric analysis of cell surface markers, morphologic analysis, and nitroblue tetrazolium reduction. In addition, inhibition of SFKs enhanced expression from retinoic acid receptor (RAR) target genes encoding CCAAT/enhancer binding protein epsilon (C/EBPepsilon), PU.1, intercellular adhesion molecule-1 (ICAM-1), and cathepsin D. Moreover, a constitutively active Src inhibited RAR-dependent transcription, whereas a kinase-dead Src exerted little effect. These studies provide the first demonstration that SFKs act to negatively regulate RA-induced gene expression and Myeloid Differentiation and suggest that the combination of SFK inhibition and RA treatment may be therapeutically beneficial in AML.
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Inhibition of Src family kinases enhances retinoic acid-induced gene expression and Myeloid Differentiation
Molecular Cancer Therapeutics, 2007Co-Authors: Michelle B. Miranda, Robert L Redner, Daniel E. JohnsonAbstract:Treatment of acute promyelocytic leukemia with retinoic acid (RA) results in Differentiation of the leukemic cells and clinical remission. However, the cellular factors that regulate RA-induced Myeloid Differentiation are largely unknown, and other forms of acute myelogenous leukemia (AML) do not respond to this Differentiation therapy. A greater understanding of the molecules that positively or negatively regulate RA-induced Differentiation should facilitate the development of more effective Differentiation therapies. In this study, we investigated the potential role of Src family kinases (SFK) in the regulation of RA-induced gene expression and Myeloid Differentiation. We report that inhibition of SFKs markedly enhanced RA-induced Differentiation in Myeloid cell lines and primary AML cells, as assessed by flow-cytometric analysis of cell surface markers, morphologic analysis, and nitroblue tetrazolium reduction. In addition, inhibition of SFKs enhanced expression from retinoic acid receptor (RAR) target genes encoding CCAAT/enhancer binding protein e (C/EBPe), PU.1, intercellular adhesion molecule-1 (ICAM-1), and cathepsin D. Moreover, a constitutively active Src inhibited RAR-dependent transcription, whereas a kinase-dead Src exerted little effect. These studies provide the first demonstration that SFKs act to negatively regulate RA-induced gene expression and Myeloid Differentiation and suggest that the combination of SFK inhibition and RA treatment may be therapeutically beneficial in AML. [Mol Cancer Ther 2007;6(12):3081–90]
Dan A. Liebermann - One of the best experts on this subject based on the ideXlab platform.
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The c‐myc apoptotic response is not intrinsic to blocking terminal Myeloid Differentiation
Journal of cellular physiology, 2008Co-Authors: Santo A. D’angelo, Dan A. Liebermann, Barbara HoffmanAbstract:It has previously been shown that deregulated c-myc blocks terminal Myeloid Differentiation and prematurely recruits both the Type I and II CD95/Fas apoptotic pathways, promoting an incompletely penetrant apoptotic response. In this work it is shown that deregulated expression of either mycER or mycER™ variants also blocked terminal Myeloid Differentiation but failed to induce the apoptotic response, demonstrating that c-myc can block Differentiation independent of the apoptotic response. The failure of the mycER™ transgene to cause the apoptotic response is associated with reduced levels of RIP1 expression, increased Mcl-1 expression and activation of both NF-kB and Akt. In addition, deregulating expression of RIP1 in M1mycER™ cells restored the apoptotic response. Thus altering c-Myc or its downstream effectors can influence the balance between apoptosis and survival, and ultimately the oncogenic potential of the c-myc oncogene. This knowledge can be exploited to manipulate the downstream effectors, such as RIP1, to promote apoptosis and drive the death of cancer cells. J. Cell. Physiol. 216: 120–127, 2008. © 2008 Wiley-Liss, Inc.
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Egr-1 abrogates the E2F-1 block in terminal Myeloid Differentiation and suppresses leukemia.
Oncogene, 2007Co-Authors: John D. Gibbs, Dan A. Liebermann, Barbara HoffmanAbstract:Deregulated growth and blocks in Differentiation collaborate in the multistage process of leukemogenesis. Previously, we have shown that ectopic expression of the zinc finger transcription factor Egr-1 in M1 myeloblastic leukemia cells promotes terminal Differentiation with interleukin-6 (IL-6). In addition, we have shown that deregulated expression of the oncogene E2F-1 blocks the Myeloid terminal Differentiation program, resulting in proliferation of immature cells in the presence of IL-6. Here it is shown that the positive regulator of Differentiation Egr-1 abrogates the E2F-1-driven block in Myeloid terminal Differentiation. The M1E2F-1/Egr-1 cells underwent G0/G1 arrest and functional macrophage maturation following treatment with IL-6. Furthermore, Egr-1 diminished the aggressiveness of M1E2F-1 leukemias and abrogated the leukemic potential of IL-6-treated M1E2F-1 cells. Previously, we reported that Egr-1 abrogated the block in terminal Myeloid Differentiation imparted by deregulated c-myc, which blocks Differentiation at a later stage than E2F-1, resulting in cells that have the characteristics of functionally mature macrophages that did not undergo G0/G1 arrest. Taken together, this work extends and highlights the tumor suppressor role of Egr-1, with Egr-1 behaving as a tumor suppressor against two oncogenes, each blocking Myeloid Differentiation by a different mechanism. These findings suggest that Egr-1 and/or Egr-1 target genes may be useful tools to treat or suppress oncogene-driven hematological malignancies.
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Terminal Myeloid Differentiation is Uncoupled from Cell Cycle Arrest
Cell cycle (Georgetown Tex.), 2007Co-Authors: John D. Gibbs, Dan A. Liebermann, Barbara HoffmanAbstract:It has been assumed that terminal Myeloid Differentiation and cell cycle arrest are coupled processes, and that prohibiting cell cycle arrest blocks Differentiation. Previously we have shown that, using the murine M1 Myeloid leukemic cell line, deregulated expression of the proto-oncogene c-myc results in cells that cannot be induced to undergo terminal Differentiation and continued to proliferate. It has also been shown that ectopic expression of Egr-1 abrogated the c-Myc block in terminal Myeloid Differentiation, yet there was no accumulation of cells in the G0/G1 phase of the cell cycle. In this study we conclusively demonstrate that M1Myc/Egr-1 cells terminally differentiate while still actively cycling and synthesizing DNA, concluding that the terminal Myeloid Differentiation program is uncoupled from growth arrest. How deregulated expression/activation of proto-oncogenes that promote cell cycle progression interferes with Differentiation and how Differentiation is regulated independently of cell cyc...
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Fos modulates Myeloid cell survival and Differentiation and partially abrogates the c-Myc block in terminal Myeloid Differentiation.
Blood, 2004Co-Authors: Marianna Shafarenko, Dan A. Liebermann, Arshad Amanullah, Bernard Gregory, Barbara HoffmanAbstract:Previously, we have shown that Fos/Jun transcription factor complexes function as positive modulators of Myeloid Differentiation. Fos, which is stably induced during normal Myeloid Differentiation, is not induced upon Differentiation of M1 myeloblastic leukemia cells. Establishing M1 cells that express a β-estradiol-conditional FosER chimera, we show that in the absence of the Differentiation inducer interleukin-6 (IL-6), Fos expression in M1 myeloblasts promoted apoptotic cell death, entailing cytochrome c release and caspase-9 activation. In contrast, in the presence of IL-6, Fos-mediated apoptosis was abrogated, and Fos promoted terminal Differentiation, increasing the sensitivity of M1 cells to be induced for Differentiation by IL-6. Fos-mediated apoptosis was accelerated by deregulated c-Myc. Furthermore, restoring Fos expression in M1 partially abrogated the block imparted by deregulated c-Myc on the Myeloid Differentiation program, increased the sensitivity of the cells to be induced for Differentiation, and curtailed their leukemic phenotype. These data provide evidence that Fos/Jun transcription factor complexes play a role in modulating both Myeloid cell survival and Differentiation and suggest that genetic lesions that alter Fos expression may cooperate with deregulated c-Myc in leukemogenesis. (Blood. 2004;103:4259-4267)
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Myeloid Differentiation (MyD) primary response genes in hematopoiesis.
Blood cells molecules & diseases, 2003Co-Authors: Dan A. Liebermann, Barbara HoffmanAbstract:Myeloid Differentiation (MyD) primary response and growth arrest DNA-damage (Gadd) genes comprise a set of overlapping genes, including known (IRF-1, EGR-1, Jun) and novel (MyD88, Gadd45a MyD118/Gadd45b, GADD45g, MyD116/Gadd34) genes, that have been cloned by virtue of being coordinately induced upon the onset of terminal Myeloid Differentiation. This review delineates the role MyD genes were found to play in blood cell development, where they function as positive regulators of terminal Differentiation, lineage specific blood cell development, and control of blood cell homeostasis, including growth inhibition and apoptosis.
