Blood Cancer Journal (Jul 2022)
BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma
- Ellen Weisberg,
- Basudev Chowdhury,
- Chengcheng Meng,
- Abigail E. Case,
- Wei Ni,
- Swati Garg,
- Martin Sattler,
- Abdel Kareem Azab,
- Jennifer Sun,
- Barbara Muz,
- Dana Sanchez,
- Anthia Toure,
- Richard M. Stone,
- Ilene Galinsky,
- Eric Winer,
- Scott Gleim,
- Sofia Gkountela,
- Alexia Kedves,
- Edmund Harrington,
- Tinya Abrams,
- Thomas Zoller,
- Andrea Vaupel,
- Paul Manley,
- Michael Faller,
- BoYee Chung,
- Xin Chen,
- Philipp Busenhart,
- Christine Stephan,
- Keith Calkins,
- Debora Bonenfant,
- Claudio R. Thoma,
- William Forrester,
- James D. Griffin
Affiliations
- Ellen Weisberg
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Basudev Chowdhury
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Chengcheng Meng
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Abigail E. Case
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Wei Ni
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Swati Garg
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Martin Sattler
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Abdel Kareem Azab
- Washington University in Saint Louis School of Medicine
- Jennifer Sun
- Washington University in Saint Louis School of Medicine
- Barbara Muz
- Washington University in Saint Louis School of Medicine
- Dana Sanchez
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Anthia Toure
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Richard M. Stone
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Ilene Galinsky
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Eric Winer
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Scott Gleim
- Novartis Pharma AG
- Sofia Gkountela
- Novartis Pharma AG
- Alexia Kedves
- Novartis Pharma AG
- Edmund Harrington
- Novartis Pharma AG
- Tinya Abrams
- Novartis Pharma AG
- Thomas Zoller
- Novartis Pharma AG
- Andrea Vaupel
- Novartis Pharma AG
- Paul Manley
- Novartis Pharma AG
- Michael Faller
- Novartis Pharma AG
- BoYee Chung
- Novartis Pharma AG
- Xin Chen
- Novartis Pharma AG
- Philipp Busenhart
- Novartis Pharma AG
- Christine Stephan
- Novartis Pharma AG
- Keith Calkins
- Novartis Pharma AG
- Debora Bonenfant
- Novartis Pharma AG
- Claudio R. Thoma
- Novartis Pharma AG
- William Forrester
- Novartis Pharma AG
- James D. Griffin
- Department of Medical Oncology, Dana-Farber Cancer Institute
- DOI
- https://doi.org/10.1038/s41408-022-00704-7
- Journal volume & issue
-
Vol. 12,
no. 7
pp. 1 – 10
Abstract
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.
