MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines

Nagel, Stefan; Meyer, Corinna; Quentmeier, Hilmar; Kaufmann, Maren; Drexler, Hans G.; MacLeod, Roderick A.F.

doi:10.1038/sj.leu.2405067

Cited by 56 publications

(48 citation statements)

References 66 publications

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“…Furthermore, the role of Scl in hematologic malignancies and the recent implication of Mef2C as a cooperating oncogene in leukemia [46][47][48][49] raise the hypothesis that Mef2C may be regulated by Scl or other bHLH factors during leukemogenesis. However, the fact that Scl is unable to bind and activate the Mef2C promoter in erythroid cells where Scl is highly expressed suggests that additional prerequisites have to be fulfilled to activate Mef2C expression.…”

Section: Discussionmentioning

confidence: 99%

Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis

Gekas

Rhodes

Gereige

et al. 2009

Blood

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The basic helix-loop-helix transcription factor stem cell leukemia gene (Scl ) is a master regulator for hematopoiesis essential for hematopoietic specification and proper differentiation of the erythroid and megakaryocyte lineages. However, the critical downstream targets of Scl remain undefined. Here, we identified a novel Scl target gene, transcription factor myocyte enhancer factor 2 C (Mef2C) from Scl fl/fl fetal liver progenitor cell lines. Analysis of Mef2C ؊/؊ embryos showed that Mef2C, in contrast to Scl, is not essential for specification into primitive or definitive hematopoietic lineages. However, adult VavCre ؉ Mef2C fl/fl mice exhibited platelet defects similar to those observed in Scldeficient mice. The platelet counts were reduced, whereas platelet size was increased and the platelet shape and granularity were altered. Furthermore, megakaryopoiesis was severely impaired in vitro. Chromatin immunoprecipitation microarray hybridization analysis revealed that IntroductionHematopoiesis, the process of blood formation, secures a continuous supply of all blood cell types throughout embryogenesis and adult life. 1 During development, hematopoiesis is segregated into distinct anatomic sites, which ensures rapid production of differentiated blood cells for the embryo's immediate needs, and the generation of definitive hematopoietic stem cells (HSCs) that are required for life-long hematopoiesis. 2 Homeostasis in the bone marrow is dependent on the faithful ability of HSCs to self-renew and to generate progenitor cells that undergo limited proliferation and give rise to terminally differentiated blood cells. These fate decisions are orchestrated by a network of transcription factors that govern stem cell-or lineage-specific gene expression programs required for proper development and function of blood cells. 1,3 During embryogenesis, the hematopoietic program is established by the basic helix-loop-helix (bHLH) transcription factor Scl/Tal1 (stem cell leukemia gene/T-cell acute lymphoblastic leukemia gene 1). 4 In the absence of Scl, blood-specific genes fail to be activated, resulting in an arrest in blood development at the hemangioblast stage. 5,6 As such, Scl knockout embryos die by E9.5. 7,8 Surprisingly, despite Scl's pivotal role in the initiation of the hematopoietic program, Scl becomes dispensable for further development and function of HSCs shortly after hematopoietic specification. 9,10 Yet, Scl is redeployed during erythroid and megakaryocytic development. In the erythroid lineage, Scl deficiency leads to inefficient erythropoiesis in both the fetal liver and bone marrow, and impaired erythroid differentiation in vitro. [9][10][11][12] In the megakaryocytic lineage, loss of Scl in adult mice results in thrombocytopenia because of defects in megakaryocyte cytoplasmic maturation and platelet shedding. 9,10,12,13 In addition, Scl-deficient progenitor cells are unable to generate megakaryocytes in vitro. 9,10 Although the critical transcriptional target genes of Scl remain poorly defined, 2 membr...

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Section: Discussionmentioning

confidence: 99%

Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis

Gekas

Rhodes

Gereige

et al. 2009

Blood

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“…21,22 Deletion of LEF1 and transcriptional deregulation of MEF2C have already been identified in T-ALL. 23,24 All of the cryptic gene lesions listed above are described here for the first time in MPAL patients. …”

Section: Array-based Comparative Genomic Hybridization Analysis Of 12mentioning

confidence: 97%

Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification

et al. 2012

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“…70 In addition, NKX2-5 binds the promoter of MEF2C and activates MEF2C transcription in T-ALL cell lines. 24,71 Recently, we identified MEF2C as a central oncogene in an immature T-ALL subgroup that shares characteristics with early T-cell precursors (ETP-ALL). In these patients, genetic aberrations were identified that target MEF2C or MEF2C-regulating transcription factors, including NKX2-5.…”

Section: Nkx2-5mentioning

confidence: 99%

“…24 MEF2C can also inhibit apoptosis by repressing NR4A1/ NUR77, which subsequently prevents transformation of BCL2 into a pro-apoptotic factor. 71 HHEX ETP-ALL is characterized by early T-cell developmental arrest 24,31,72 and ectopic expression of LMO2, LYL1 and the NKL homeobox gene HHEX. 24,31 We have previously demonstrated that LMO, LYL1 and HHEX are transcriptional targets of MEF2C.…”

Section: Nkx2-5mentioning

confidence: 99%

NKL homeobox genes in leukemia

2011

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MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines

Cited by 56 publications

References 66 publications

Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis

Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis

Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification

NKL homeobox genes in leukemia

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