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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Transgenic
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Polycomb Repressive Complex 1 / antagonists & inhibitors
  • Polycomb Repressive Complex 1 / genetics
  • Polycomb Repressive Complex 1 / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Thiazoles / pharmacology
  • U937 Cells
  • Xenograft Model Antitumor Assays

Substances

  • AF10-CALM fusion protein, human
  • BMI1 protein, human
  • Bmi1 protein, mouse
  • Heterocyclic Compounds, 2-Ring
  • Oncogene Proteins, Fusion
  • PTC-209
  • Proto-Oncogene Proteins
  • Thiazoles
  • Polycomb Repressive Complex 1