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 Blood, 17 September 2009, Vol. 114, No. 12, pp. 2476-2488.
Prepublished online as a Blood First Edition Paper on July 22, 2009; DOI 10.1182/blood-2008-05-158196.

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MYELOID NEOPLASIA

Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C

Maike Schwieger1,*, Andrea Schüler1,*, Martin Forster1, Afra Engelmann1, Michael A. Arnold2, Ruud Delwel3, Peter J. Valk3, Jürgen Löhler1, Robert K. Slany4, Eric N. Olson2, and Carol Stocking1

1 Heinrich-Pette-Institute, Hamburg, Germany; 2 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas; 3 Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands; and 4 Department of Genetics, University of Erlangen, Erlangen, Germany

Acute myelogenous leukemia is driven by leukemic stem cells (LSCs) generated by mutations that confer (or maintain) self-renewal potential coupled to an aberrant differentiation program. Using retroviral mutagenesis, we identified genes that generate LSCs in collaboration with genetic disruption of the gene encoding interferon response factor 8 (Irf8), which induces a myeloproliferation in vivo. Among the targeted genes, we identified Mef2c, encoding a MCM1-agamous-deficiens-serum response factor transcription factor, and confirmed that overexpression induced a myelomonocytic leukemia in cooperation with Irf8 deficiency. Strikingly, several of the genes identified in our screen have been reported to be up-regulated in the mixed-lineage leukemia (MLL) subtype. High MEF2C expression levels were confirmed in acute myelogenous leukemia patient samples with MLL gene disruptions, prompting an investigation of the causal interplay. Using a conditional mouse strain, we demonstrated that Mef2c deficiency does not impair the establishment or maintenance of LSCs generated in vitro by MLL/ENL fusion proteins; however, its loss led to compromised homing and invasiveness of the tumor cells. Mef2c-dependent targets included several genes encoding matrix metalloproteinases and chemokine ligands and receptors, providing a mechanistic link to increased homing and motility. Thus, MEF2C up-regulation may be responsible for the aggressive nature of this leukemia subtype.


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