Modulation of the myeloid differentiation block in acute myeloid leukemia II

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Current treatments for acute myeloid leukemia (AML) are myelotoxic and leave patients unprotected against infectious complications for several weeks with often fatal consequences. To quickly restore immune function in AML patients, we need to directly induce differentiation of leukemic blasts to functioning immune cells. The major obstacle of such treatments has been our insufficient understanding of the differentiation block in AML, exemplified by the resistance to retinoic acid (ATRA) signaling. During the last three years we have made considerable progress in understanding the components of blocked myeloid differentiation by studying the mechanism of the oncogene MN1. MN1 induces ATRA resistance in human cells and transforms human hematopoietic progenitor cells. MN1 represses genes of the immune response signature in concert with the oncogene MEIS1, but not with RARA, the receptor for ATRA. Moreover, we found evidence that RARA is displaced by MN1 and therefore hypothesize that RARA displacement induces resistance to retinoic acid signaling in AML. We propose to 1) verify RARA displacement in primary human AML cells, 2) functionally characterize the proteins that displace RARA and 3) develop lipid/siRNA formulations as differentiation-inducing therapeutic targets. Our project addresses a critical aspect of leukemogenesis that is poorly understood so far and may have wider implications for other areas like differentiation of induced pluripotent stem cells to functioning immune cells.