Hematopoietic malignancies result from dysregulated self-renewal pathways and an altered differentiation program. Acute myeloid leukemia (AML) is characterized by the abnormal development of blood cells in the myeloid lineage. Our laboratory and others have demonstrated that the <i>MUSASHI2</i> RBP expression predicts a poor prognosis and drives the aggressiveness of myeloid leukemia. We identified that MUSASHI2 controls critical MLL regulated transcription factors including <i>Hoxa9</i>, Myc and Ikzf2. Despite extensive studies implicating Myc and Hoxa9 in leukemia, the role for Ikzf2 in myeloid leukemia is not known. Ikzf2 is a member of the Ikaros transcription factor family and regulates lymphocyte development by controlling regulatory T-cell function. Ikzf2 is highly expressed in Hematopoietic Stem Cells (HSC) and is deleted in 50% of hypodiploid B-ALLs. In contrast to IKZF2 acting as a tumor suppressor gene in lymphoid malignancies, we have identified it as a novel dependency in myeloid leukemia. Additionally, studies from our laboratory and others have indicated that inhibiting the MUSASHI family could provide a novel therapeutic strategy in myeloid leukemia. Towards this goal, we have established a screening platform that has identified small molecules that block MSI binding to their target mRNAs. We have validated one of these compounds and have demonstrated that inhibiting MUSASHI-2 drives differentiation and apoptosis of mouse and human AML cells. These data provide the initial studies and a proof of concept that pharmacologically targeting MUSASHI-2 could be a viable strategy in acute myeloid leukemia.

Towards therapeutic targeting of the MUSASHI RNA binding protein network

256th National Meeting (2018)

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