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bioRxiv · 10.1101/524066

Acute Myeloid Leukemia Driven by the CALM-AF10 Fusion Gene is Dependent on BMI1

Barbosa, K.·Ghosh, A.·Deshpande, A.·Chen, B.-R.·Sun, Y.·Weetall, M.·Armstrong, S. A.·Bohlander, S. K.·Deshpande, A. J.
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Abstract

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.

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Barbosa, K., Ghosh, A., Deshpande, A., Chen, B.-R., Sun, Y., Weetall, M., Armstrong, S. A., Bohlander, S. K., Deshpande, A. J.. 2019-01-18. Acute Myeloid Leukemia Driven by the CALM-AF10 Fusion Gene is Dependent on BMI1. https://doi.org/10.1101/524066

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