BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma

  • Blood Cancer J. 2022 Jul 19;12(7):110. doi: 10.1038/s41408-022-00704-7.
Ellen Weisberg   #  1  2 ,  Basudev Chowdhury   #  3  4 ,  Chengcheng Meng   #  3 ,  Abigail E Case  3 ,  Wei Ni  3  4 ,  Swati Garg  3  4 ,  Martin Sattler  3  4 ,  Abdel Kareem Azab  5 ,  Jennifer Sun  5 ,  Barbara Muz  5 ,  Dana Sanchez  3 ,  Anthia Toure  3 ,  Richard M Stone  3  4 ,  Ilene Galinsky  3 ,  Eric Winer  3  4 ,  Scott Gleim  6 ,  Sofia Gkountela  6 ,  Alexia Kedves  6  7 ,  Edmund Harrington  6 ,  Tinya Abrams  6 ,  Thomas Zoller  6 ,  Andrea Vaupel  6 ,  Paul Manley  6 ,  Michael Faller  6 ,  BoYee Chung  6 ,  Xin Chen  6 ,  Philipp Busenhart  6 ,  Christine Stephan  6 ,  Keith Calkins  6 ,  Debora Bonenfant  6 ,  Claudio R Thoma  6 ,  William Forrester  6 ,  James D Griffin  8  9
Affiliations
  • 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 2. Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
  • 3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4. Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 5. Washington University in Saint Louis School of Medicine, St. Louis, MO, USA.
  • 6. Novartis Pharma AG, Basel, Switzerland.
  • 7. Alphina Therapeutics, Westport, CT, USA.
  • 8. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 9. Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 35853853 DOI: 10.1038/s41408-022-00704-7
Abstract

Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas Apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with Other agents, as a novel strategy for acute leukemias and MM.

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