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

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 ge-netic 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 tran-scription factor, and confirmed that over-expression induced a myelomonocytic leukemia in cooperation with Irf8 defi-ciency. Strikingly, several of the genes identified in our screen have been re-ported 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 defi-ciency does not impair the establishment or maintenance of LSCs generated in vitro by MLL/ENL fusion proteins; how-ever, its loss led to compromised homing and invasiveness of the tumor cells. Mef2c-dependent targets included sev-eral genes encoding matrix metallopro-teinases and chemokine ligands and re-ceptors, providing a mechanistic link to increased homing and motility. Thus, MEF2C up-regulation may be responsible for the aggressive nature of this leukemia subtype. (Blood. 2009;114:2476-2488