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 Blood, 1 May 2008, Vol. 111, No. 9, pp. 4532-4541.
Prepublished online as a Blood First Edition Paper on March 7, 2008; DOI 10.1182/blood-2007-10-116343.

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HEMATOPOIESIS AND STEM CELLS

The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate

Andrea Schüler1,*, Maike Schwieger1,*, Afra Engelmann1, Kristoffer Weber1, Stefan Horn1, Ursula Müller1, Michael A. Arnold2, Eric N. Olson2, and Carol Stocking1

1 Heinrich-Pette-Institute, Hamburg, Germany; and 2 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas

Mef2c is a MADS (MCM1-agamous–deficient serum response factor) transcription factor best known for its role in muscle and cardiovascular development. A causal role of up-regulated MEF2C expression in myelomonocytic acute myeloid leukemia (AML) has recently been demonstrated. Due to the pronounced monocytic component observed in Mef2c-induced AML, this study was designed to assess the importance of Mef2c in normal myeloid differentiation. Analysis of bone marrow (BM) cells manipulated to constitutively express Mef2c demonstrated increased monopoiesis at the expense of granulopoiesis, whereas BM isolated from Mef2c{Delta}/– mice showed reduced levels of monocytic differentiation in response to cytokines. Mechanistic studies showed that loss of Mef2c expression correlated with reduced levels of transcripts encoding c-Jun, but not PU.1, C/EBP{alpha}, or JunB transcription factors. Inhibiting Jun expression by short-interfering RNA impaired Mef2c-mediated inhibition of granulocyte development. Moreover, retroviral expression of c-Jun in BM cells promoted monocytic differentiation. The ability of Mef2c to modulate cell-fate decisions between monocyte and granulocyte differentiation, coupled with its functional sensitivity to extracellular stimuli, demonstrate an important role in immunity—and, consistent with findings of other myeloid transcription factors, a target of oncogenic lesions in AML.


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