TY - JOUR
T1 - The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate
AU - Schüler, Andrea
AU - Schwieger, Maike
AU - Engelmann, Afra
AU - Weber, Kristoffer
AU - Horn, Stefan
AU - Müller, Ursula
AU - Arnold, Michael A.
AU - Olson, Eric N.
AU - Stocking, Carol
PY - 2008/5/1
Y1 - 2008/5/1
N2 - Mef2c is a MADS (MCMI-agamousdeficient 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 Mef2cinduced 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 Mef2cΔ/- 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/EBPα 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.
AB - Mef2c is a MADS (MCMI-agamousdeficient 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 Mef2cinduced 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 Mef2cΔ/- 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/EBPα 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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U2 - 10.1182/blood-2007-10-116343
DO - 10.1182/blood-2007-10-116343
M3 - Article
C2 - 18326819
AN - SCOPUS:47149093377
SN - 0006-4971
VL - 111
SP - 4532
EP - 4541
JO - Blood
JF - Blood
IS - 9
ER -