The O-Linked N-Acetylglucosamine Transferase Modifies HOXA9 and Inhibits HOXA9-Driven Immortalization

The homeodomain-containing transcription factor HOXA9 is a core element of the HOXA9 enhanceosome, a critical DNA-protein complex that regulates hematopoietic stem cell self-renewal during hematopoiesis. Several genetic mutations observed in acute myeloid leukemia (AML) patients, including MLL translocations, are associated with aberrant up regulation of HOXA9, thus disrupting the hematopoietic balance towards leukemogenesis. While analyses of HOXA9 and cofactors have uncovered fundamental aspects of the mechanisms through which these proteins mediate their functions, questions remain. For example, what molecular mechanisms contribute to switching HOXA9 enhanceosomes off during myeloid differentiation? Could these mechanisms be targeted for the therapeutic benefit of leukemia patients? Characterization of the molecular interactions in which HOXA9 enhanceosome proteins are involved should shed light on the mechanisms that govern these proteins during both normal hematopoiesis and leukemogenesis. We recently discovered that HOXA9 interacts physically with OGT, the only O-linked N-acetyl glucosamine transferase in humans. We also demonstrated that HOXA9 is O-GlcNAcylated by OGT. Investigation of the functional relevance of this interaction to HOXA9-driven leukemogenesis is currently under way using interaction- and O-GlcNAcylation-deficient alleles of HOXA9 in a colony formation assay. Our preliminary results suggest that OGT inhibits HOXA9’s ability to transform primary bone marrow cells, thus suggesting OGT is a potential tumor suppressor of HOXA9-driven leukemogenesis. Current efforts focus on further dissecting the molecular interplay occurring between HOXA9 and OGT on chromatin, its impact on the regulation of HOXA9 targets and its role in HOXA9-driven leukemogenesis. Work is also under way to identify factors involved in the OGT-mediated regulation of HOXA9 enhanceosomes.