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

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.

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

“…Inactivating mutations in PICALM result in defective hematopoiesis and iron uptake in mice, suggesting an important role of PICALM within the hematopoietic system. 36,37 PICALM-MLLT10 leukemia is also dependent on expression of BMI1 and HOXA5, as genetic depletion of either target results in failure of PICALM-MLLT10 to transform murine hematopoietic precursor cells. 37,38 Two C-terminal domains of PICALM, the NES and clathrin-binding domain ( Figure 2B Interestingly, the NES of DDX3X is also invariably retained in DDX3X-MLLT10 ( Figure 2C), but further functional studies are not available.…”

“…36,37 PICALM-MLLT10 leukemia is also dependent on expression of BMI1 and HOXA5, as genetic depletion of either target results in failure of PICALM-MLLT10 to transform murine hematopoietic precursor cells. 37,38 Two C-terminal domains of PICALM, the NES and clathrin-binding domain ( Figure 2B Interestingly, the NES of DDX3X is also invariably retained in DDX3X-MLLT10 ( Figure 2C), but further functional studies are not available. 15 The PICALM clathrin-binding domain is integral in clathrin-mediated endocytosis, and deletion of the clathrin-binding domain from PICALM-MLLT10 alters myeloid disease phenotype in murine xenotransplantation models.…”

“…Specifically, increased expression of COMMD3, BMI1, DNAJC1 and SPAG6 are consistently observed across studies, all located centromeric to MLLT10 on chromosome 10 (Figure 3). 31,68,73 Genomic and pharmacological depletion of the polycomb group protein BMI1 inhibits PICALM-MLLT10-driven AML 37 include allogeneic hematopoietic stem cell transplantation. 77,78 Small studies indicate that allogeneic HSCT may provide disease-free survival benefit in TCR neg T-ALL or ETP-ALL MLLT10r patients, but larger cohort studies are required.…”

“…2,12,15 Data regarding therapeutic sensitivity of MLLT10r acute leukemia is lacking, owing to the rarity of these fusions, but DOT1L and BMI1 inhibition both represent promising targets in the treatment of MLLT10r acute leukemia, based on preclinical models. 37,79 Other potential candidates include histone deacetylase (HDAC) inhibitors and the DNA demethylating agent azacytidine. These agents have preclinical efficacy in KMT2Ar leukemia, 68 and may have promise in MLLT10r cases, based on the similar gene expression profile shared by the two genomic subtypes.…”

“…Further preclinical work is required to validate the efficacy of DOT1L inhibition in MLLT10r AML and T-ALL, but DOT1L inhibition is currently the most advanced and promising therapeutic target for MLLT10r acute leukemia.7 | BMI1 INHIBITORSPICALM-MLLT10 AML is dependent on expression of BMI1, and murine and human models of PICALM-MLLT10-driven leukemias are sensitive to BMI1 inhibition 31,37,73. BMI1 is a polycomb group protein, responsible for the epigenetic repression of developmentally important genes, including CDKN2A locus genes p16 INK4A and p14 ARF , critical in the regulation of cell cycle progression and self-renewal of stem cells 37,84. Both genetic and pharmacological inhibition of BMI1impedes PICALM-MLLT10-driven myeloid transformation, and inhibits proliferation of human PICALM-MLLT10 AML cells in vitro and in murine xenotransplantation models.…”