The function of the HoxA9 transcription factor is of critical interest in human acute myeloid leukemia (AML) since oncogenic activation of HoxA9 is induced by multiple chromosomal translocations; however, independent studies indicate that the expression level of HoxA9 is prognostic in human AML lacking these chromosomal abnormalities. Thus, an understanding of HoxA9 signaling would significantly impact patients with AML. Importantly, the direct transcriptional targets of HoxA9 and thus mechanism of HoxA9-mediated transformation remain largely unknown. The Growth factor independent-1 (Gfi1) transcriptional repressor is known to induce granulopoiesis, inhibits myeloid progenitor proliferation, and is mutated in patients with severe congenital neutropenia (SCN). SCN patients are at increased risk for AML. We have recently shown that 1) Gfi1 represses HoxA9, Meis1 and Pbx1 expression, 2) Gfi1 and HoxA9 demonstrate dramatic epistatic relationships, and 3) Gfi1 loss of function is potently preleukemic. The antagonism between Gfi1 and HoxA9 is conserved to Drosophila, and our preliminary data indicate that in mammalian myeloid progenitors centers upon the expression of microRNA encoding genes. We hypothesize that these microRNA mediate Hox-based leukemic signaling, and that specific microRNA inhibitors abort the maintenance of Hox-based leukemia initiating cells. The proposed research will delineate the functional role of microRNA as molecular signaling effectors/clients of Hox-based leukemia oncoproteins.
Acute myeloid leukemia, a cancer of the blood, accounts for 1.2% of cancer deaths in the United States; however, rates are expected to increase as the population ages and successful therapeutics are expected to benefit patients with leukemia and abnormal hematopoiesis. The proposed work may be considered both an examination of oncogenic signaling, and a pre-clinical proof of principle for the use of microRNA inhibitors in the treatment of leukemia. microRNA antagonists are being developed for clinical use by several companies and the proposed experiments are anticipated to be pioneering work to move the concept forward.
