TY - JOUR T1 - Acute Myeloid Leukemia Driven by the CALM-AF10 Fusion Gene is Dependent on BMI1 JF - bioRxiv DO - 10.1101/524066 SP - 524066 AU - Karina Barbosa AU - Anwesha Ghosh AU - Anagha Deshpande AU - Bo-Rui Chen AU - Younguk Sun AU - Marla Weetall AU - Scott A. Armstrong AU - Stefan K. Bohlander AU - Aniruddha J. Deshpande Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/01/18/524066.abstract N2 - A subset of acute myeloid and lymphoid leukemia cases harbor a t(10;11)(p13;q14) translocation resulting in the CALM-AF10 fusion gene. Standard chemotherapeutic strategies are often ineffective in treating patients with CALM-AF10 fusions. Hence, there is an urgent need to identify molecular pathways dysregulated in CALM-AF10-positive leukemias which may lay the foundation for novel targeted therapies. Here we demonstrate that the Polycomb Repressive Complex 1 gene BMI1 is consistently overexpressed in adult and pediatric CALM-AF10-positive leukemias. We demonstrate that genetic Bmi1 depletion abrogates CALM-AF10-mediated transformation of murine hematopoietic stem and progenitor cells (HSPCs). Furthermore, CALM-AF10-positive murine and human AML cells are profoundly sensitive to the small-molecule BMI1 inhibitor PTC209 as well as to PTC596, a compound in clinical development that has been shown to result in downstream degradation of BMI1 protein. PTC-596 significantly prolongs survival of mice injected with a human CALM-AF10 cell line in a xenograft assay. In summary, these results validate BMI1 as a bonafide candidate for therapeutic targeting in AML with CALM-AF10 rearrangements. ER -