Epigenetic Signaling Is Required for HoxA9-Based Leukemic Transformation.

Abstract 3966

Poster Board III-902

Since oncogenic activation of HoxA9 is induced by multiple chromosomal translocations affecting MLL1 (11q23)(e.g. MLL-Af9) or Nup98 (11p15)(e.g. Nup98-HoxA9 or Nup98-Nsd1), the function of the HoxA9 transcription factor is of critical interest in human acute myeloid leukemia (AML). HoxA9 forms heterodimeric DNA binding complexes with members of the Pbx and/or Meis family of homeodomain proteins. Importantly, the direct transcriptional targets of endogenous HoxA9 that mediate transformation remain largely unknown. The Growth factor independent-1 (Gfi1) transcriptional repressor is known to induce granulopoiesis and inhibit myeloid progenitor proliferation. GFI1 is mutated in patients with severe congenital neutropenia (SCN). SCN patients are at increased risk for AML. In a transcriptional circuit conserved to Drosophila, we have recently shown that Gfi1 represses HoxA9, Meis1 and Pbx1 expression, that Gfi1 and HoxA9 demonstrate dramatic epistatic relationships, and that Gfi1 loss of function is potently preleukemic. Our new bioinformatic, biochemical and expression data reveal microRNA genes to be targets of endogenous HoxA9 versus Gfi1 antagonism. Moreover, these miR are activated by Hox-signaling leukemia oncoproteins. Next, in both murine leukemia models and primary human AML samples, antagomir-mediated inhibition of microRNA function specifically disrupts oncogenic signaling by HoxA9, Nup98-HoxA9 and MLL-Af9 (but not AML-ETO which does not signal through HoxA9). In vivo, antagomir treatment blocked MLL-Af9-initiated leukemia lethality. These data establish microRNA genes as functional downstream targets of endogenous HoxA9, and implicate epigenetic signaling as critical client/mediators of Hox-based leukemia oncoproteins.