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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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Submitted October 5, 2007
Accepted February 23, 2008
The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate
Andrea Schuler, Maike Schwieger, Afra Engelmann, Kristoffer Weber, Stefan Horn, Ursula Muller, Michael A. Arnold, Eric N. Olson, and Carol Stocking*
Molecular Pathology, Heinrich-Pette-Institute, Hamburg, Germany
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, United States
* Corresponding author; email: stocking{at}hpi.uni-hamburg.de.
Mef2c is a MADS transcription factor best-known for its role in muscle and cardiovascular development. A causal role of upregulated 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 BM cells manipulated to constitutively express Mef2c demonstrated increased monopoiesis at the expense of granulopoiesis, whereas BM isolated from Mef2c /- 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 , 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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