E2a/Pbx1 oncogene inhibits terminal differentiation but not myeloid potential of pro-T cells

Bourette, Roland P.; Mf, Grasset; Mouchiroud, Guy

doi:10.1038/sj.onc.1209777

Cited by 14 publications

(23 citation statements)

References 67 publications

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“…In support to this hypothesis, we recently observed that differentiation response to M-CSF of conditionally immortalized hematopoietic progenitors could be shifted from macrophage to granulocyte lineage by addition of U0126. 37 Therefore, current data support the conclusion that myeloid progenitor cell fate depends exclusively on the activation levels of the MAPK pathway.…”

Section: Sfk and Mapk Regulate Monocytic Development Of Mouse Bone Masupporting

confidence: 74%

Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2

et al. 2007

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Macrophage colony-stimulating factor (M-CSF) has been found to be involved in multiple developmental processes, especially production of cells belonging to the mononuclear phagocyte system. The decision of myeloid progenitor cells to commit to differentiation depends on activation levels of the mitogenactivated protein kinases (MAPK), ERK1 and ERK2. Using the murine myeloid progenitor cell line FD-Fms, we show here that persistent activity of Src-family kinases (SFK) is necessary for FD-Fms cell differentiation to macrophages in response to M-CSF. Chemical inhibition of SFK blocked FD-Fms cell differentiation while it caused strong inhibition of the late phosphorylation of phospholipase C (PLC)-c2 and MAPK. The PLC inhibitor U73122, previously shown to block M-CSF-induced differentiation, strongly decreased long-term MAPK phosphorylation. Interestingly, inhibiting SFK with SU6656 or the MAPK kinases MEK with U0126 significantly impaired development of mononuclear phagocytes in cultures of mouse bone marrow cells stimulated with M-CSF. Collectively, results support a model in which SFK are required for sustained PLC activity and MAPK activation above threshold required for commitment of myeloid progenitors to macrophage differentiation.

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Section: Sfk and Mapk Regulate Monocytic Development Of Mouse Bone Masupporting

confidence: 74%

Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2

et al. 2007

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“…18 Activation of Src family kinases by the MCSFR also leads to PLC␥2 activation, and Src inhibition prevents FDC-P1 differentiation in response to M-CSF. 19 Consistent with a specific role during monopoieisis, we find that M-CSF, but not G-CSF, activates PLC␥2.…”

Section: Discussionmentioning

confidence: 99%

“…16 Use of the U0126 MEK inhibitor to block ERK activation prevents FDC-P1 cells from differentiating into monocytes in response to M-CSF, 17 induces bone marrow cells immortalized with the E2A-Pbx1 oncogene to differentiate into granulocytes instead of monocytes in M-CSF, and increases production of granulocytes from normal marrow mononuclear cells placed in liquid culture. 18,19 Conversely, the same MEK inhibitor interfered with both granulocytic differentiation of the 32Dcl3 cell line and monocytic differentiation of M1 cells. 20 To help define the role of cytokine receptor signaling in monocyte versus granulocyte lineage commitment, we reasoned that it would be useful to directly compare GCSFR and MCSFR signals in the same cellular context.…”

Section: Introductionmentioning

confidence: 99%

M-CSF elevates c-Fos and phospho-C/EBPα(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification

Jack

Zhang

Friedman

2009

Blood

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The role of hematopoietic cytokines in lineage commitment remains uncertain. To gain insight into the contribution of cytokine signaling to myeloid lineage specification, we compared granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) signaling in Ba/F3 cells expressing both the G-CSF and M-CSF receptors and in lineage-negative murine marrow cells. G-CSF and M-CSF serve as prototypes for additional cytokines that also influence immature myeloid cells. G-CSF specifically activated signal transducer and activator of transcription 3 and induced Src homology region 2 domain-containing phosphatase 2 (SHP2) phosphorylation, whereas M-CSF preferentially activated phospholipase Cγ2, and thereby extracellular signal-regulated kinase (ERK), to stabilize c-Fos and stimulate CCAAT/enhancer-binding protein (C/EBP)α(S21) phosphorylation. In contrast, activation of Jun kinase or c-Jun was similar in response to either cytokine. Inhibition of ERK prevented induction of c-Fos by M-CSF and reduced C/EBPα phosphorylation and formation of colony-forming unit–monocytes. SHP2 inhibition reduced ERK activation in G-CSF, but not M-CSF, and reduced colony-forming unit–granulocytes, underscoring divergent pathways to ERK activation. Phorbol ester mimicked the effect of M-CSF, activating ERK independent of SHP2. In summary, M-CSF activates ERK more potently than G-CSF, and thereby induces higher levels of c-Fos and phospho-C/EBPα(S21), which may directly interact to favor monopoiesis, whereas G-CSF activates signal transducer and activator of transcription 3 and SHP2, potentially shifting the balance to granulopoiesis via gene induction by C/EBPα homodimers and via effects of SHP2 on regulators besides ERK.

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“…The results correspond well to the experimental data indicating a common prevalence of RUNX motif in all classes and additional motifs, of RUNX1-cooperating TFs, including GATA, AP-1, and ETS, which were biased toward class specificity. Importantly, their enrichment varied according to megakaryocytic differentiation stages: GATA at K562 constitutive sites, AP-1 at TPA-induced sites, and ETS at CMK-specific sites.Interestingly, when RUNX1 ChIP-seq data for Jurkat T cells 40 were included in the co-occurrence analysis, it was found that AP-1 motif was significantly under-represented, whereas a pronounced enrichment for the motif of TF PBX1B (GATGTG) was noted (supplemental Figure 8), 44,45 raising the possibility that, in T cells, RUNX1 also cooperates with PBX1B. Comparison of the overall RUNX1-binding profile showed that the highest overlap with T cells was found among CMK ChIP-seq data (supplemental Figure 9).…”

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confidence: 99%

Dynamic combinatorial interactions of RUNX1 and cooperating partners regulates megakaryocytic differentiation in cell line models

Pencovich¹,

Jaschek

Tanay

et al. 2011

Blood

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Specific interactions of transcription factors (TFs) with their targets are crucial for specifying gene expression programs during cell differentiation. How specificity is maintained despite limited selectivity of individual TF-DNA interactions is not fully understood. RUNX1 TF is among the most frequently mutated genes in human leukemia and an important regulator of megakaryopoiesis. We used megakaryocytic cell lines to characterize the network of RUNX1 targets and cooperating TFs in differentiating megakaryocytes and demonstrated how dynamic partnerships between RUNX1 and cooperating TFs facilitated regulatory plasticity and specificity during this process. After differentiation onset, RUNX1 directly activated a large number of genes through interaction with preexisting and de novo binding sites. Recruitment of RUNX1 to de novo occupied sites occurred at H3K4me1-marked preprogrammed enhancers. A significant number of these de novo bound sites lacked RUNX motif but were occupied by AP-1 TFs. Reciprocally, AP-1 TFs were up-regulated by RUNX1 after 12-O-tetradecanoylphorbol-13-acetate induction and recruited to RUNX1-occupied sites lacking AP-1 motifs. At other differentiation stages, additional combinatorial interactions occurred between RUNX1 and its coregulators, GATA1 and ETS. The findings suggest that in differentiating megakaryocytic cell lines, RUNX1 cooperates with GATA1, AP-1, and ETS to orchestrate cell-specific transcription programs through dynamic TF partnerships. (Blood. 2011;117(1): e1-e14) IntroductionThe RUNX transcription factors (TFs) are key regulators of cell lineage and differentiation in several important developmental pathways. They regulate transcription in a context-dependent manner through binding to the consensus core DNA sequence PyGPyGGT. 1 RUNX1 functions as key regulator in embryonic and adult hematopoiesis. 2 Consistent with its important roles, haploinsufficiency, resulting from heterozygous loss-of-function mutations, is associated with familial platelet disorder and predisposition to acute myeloid leukemia (FPD-AML). 3,4 Sporadic heterozygous mutations in RUNX1 are also leukemogenic. 5,6 RUNX1 resides on human chromosome 21, and chromosomal translocations involving RUNX1, including 8;21,3;21,and 12;21, are among the most frequent leukemia-associated translocations. 7 In addition, patients with Down syndrome (DS), the phenotypic manifestation of trisomy 21, have 500 fold-increased risk of developing acute megakaryoblastic leukemia (DS-AMKL/AML-M7) relative to normal persons. 8 RUNX1 plays an important role in megakaryopoiesis, the process leading to production of megakaryocytes, the polyploid precursors of platelets. 9,10 Megakaryocytes share a common precursor with erythrocytes known as the megakaryocyte erythroid progenitor, which gives rise to both megakaryocytic and erythroid lineages. 9,10 Overexpression of RUNX1 in myeloid cell lines induces megakaryocytic differentiation, 11,12 whereas induced Runx1 deficiency in bone marrow results in impaired megakaryocytic maturation a...

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E2a/Pbx1 oncogene inhibits terminal differentiation but not myeloid potential of pro-T cells

Cited by 14 publications

References 67 publications

Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2

Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2

M-CSF elevates c-Fos and phospho-C/EBPα(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification

Dynamic combinatorial interactions of RUNX1 and cooperating partners regulates megakaryocytic differentiation in cell line models

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