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

Barbosa, Karina; Deshpande, Anagha; Chen, Bo-Rui; Ghosh, Anwesha; Sun, Younguk; Dutta, Sayantanee; Weetall, Marla; Dixon, Jesse; Armstrong, Scott A.; Bohlander, Stefan K. und Deshpande, Aniruddha J. (2019): Acute myeloid leukemia driven by the CALM-AF10 fusion gene is dependent on BMI1. In: Experimental Hematology, Bd. 74: S. 42-51

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 BMIl is consistently overexpressed in adult and pediatric CALM-AF10-positive leukemias. We demonstrate that genetic Bmil 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. (C) 2019 Published by Elsevier Inc. on behalf of ISEH - Society for Hematology and Stem Cells.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0301-472X
• Sprache: Englisch