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 smallmolecule 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.
INTRODUCTIONAcute leukemia patients often harbor genomic translocation events that give rise to oncogenic fusion proteins (Greaves & Wiemels, 2003;Rowley, 1999). The t(10;11)(p13;q14) translocation is a recurrent, balanced translocation observed in human leukemia, which gives rise to the CALM-AF10 fusion protein (Bohlander et al., 2000;D Caudell & Aplan, 2008). Patients harboring the CALM-AF10 fusion have a particularly poor prognosis (Dreyling et al., 1998;Narita et al., 1999). Standard chemotherapeutic strategies are often not very effective 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.The N'-terminal partner of the fusion -CALM/PICALM, is a ubiquitously expressed component of the clathrin-mediated endocytosis (CME) pathway (Tebar, Bohlander, & Sorkin, 1999).