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Exp Hematol. 2019 Jun;74:42-51.e3. doi: 10.1016/j.exphem.2019.04.003. Epub 2019 May 13.

Acute myeloid leukemia driven by the CALM-AF10 fusion gene is dependent on BMI1.

Author information

1
Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
2
Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
3
PTC Therapeutics, South Plainfield, NJ.
4
Peptide Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA.
5
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
6
Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. Electronic address: s.bohlander@auckland.ac.nz.
7
Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA. Electronic address: adeshpande@sbpdiscovery.org.

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 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.

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