BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Chromatin Biology

Background:

• Bromodomain-containing protein 9 (BRD9) is a key component of the ncBAF SWI/SNF chromatin remodeling complex.
• BRD9 is a validated therapeutic target in certain leukemias and sarcomas.

Purpose of the Study:

• To investigate the dependency on BRD9 in various hematological malignancies.
• To evaluate the therapeutic potential of BRD9 inhibition in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM).

Main Methods:

• Utilized novel small molecule inhibitors and degraders targeting BRD9.
• Employed RNA interference (RNAi) for BRD9 depletion.
• Conducted RNA-sequencing (RNA-seq) analysis to identify affected signaling pathways.

Main Results:

• BRD9 depletion induced terminal differentiation in AML cells.
• Apoptosis was the predominant response in ALL and MM cells following BRD9 depletion.
• BRD9 inhibition affected common pathways including inflammation, cell adhesion, DNA repair, and cell cycle progression.
• BRD9 degradation enhanced the efficacy of existing chemotherapeutic and targeted agents against AML, ALL, and MM.

Conclusions:

• BRD9 is a critical dependency in AML, ALL, and MM.
• Targeting BRD9, either alone or in combination therapies, represents a promising novel strategy for treating these hematological malignancies.
• Further clinical development of BRD9-targeting agents is warranted.