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 A. Toure, Richard M. Stone, Ilene Galinsky, Eric S. Winer, Scott Gleim, Sofia Gkountela, Alexia T. Kedves, Edmund Harrington, Tinya J. Abrams, Thomas Zöller, Andrea Vaupel, Paul W. Manley, Michael Faller, BoYee Chung, Xin Chen, Philipp Busenhart, Christine Stephan, Keith Calkins, Débora Bonenfant, Claudio R. Thoma, William C. Forrester, James D. Griffin
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.