| First Author | Barbosa K | Year | 2019 |
| Journal | Exp Hematol | Volume | 74 |
| Pages | 42-51.e3 | PubMed ID | 31022428 |
| Mgi Jnum | J:294492 | Mgi Id | MGI:6456454 |
| Doi | 10.1016/j.exphem.2019.04.003 | Citation | Barbosa K, et al. (2019) Acute myeloid leukemia driven by the CALM-AF10 fusion gene is dependent on BMI1. Exp Hematol 74:42-51.e3 |
| abstractText | 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 sensitive to the small-molecule BMI1 inhibitor PTC-209 as well as to PTC-596, 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 bona fide candidate for therapeutic targeting in AML with CALM-AF10 rearrangements. |
