Year: 2026
Type: article
Abstract: BAF complexes are ATP-dependent chromatin remodelers that govern gene expression and cellular identity. The non-canonical BAF (ncBAF) complex, with BRD9 as its signature component, orchestrates chromatin remodeling essential for balanced hematopoiesis. BRD9 loss disrupts enhancer-promoter interactions and CTCF-mediated chromatin architecture, causing myeloid skewing, impaired lymphoid differentiation, and diminished hematopoietic stem cell (HSC) fitness-phenotypes recapitulating physiological aging. This mechanism underlies aging-related pathologies such as myelodysplastic syndromes (MDS), in which spliceosomal mutations in SF3B1 trigger aberrant BRD9 splicing and destabilize its mRNA. Remarkably, BRD9 exhibits context-dependent functions: its depletion consistently promotes differentiation and apoptosis in myeloid leukemias, contrasting its differential roles in myeloid differentiation in adult versus fetal hematopoiesis. Thus, BRD9 mechanistically links spliceosomal dysfunction to chromatin dysregulation, bridging aging-associated disease and malignant transformation through context-dependent roles. Among the diverse assemblies of BAF family, these findings position the BRD9-ncBAF axis as both a critical determinant of hematopoietic fate decisions and a promising therapeutic target in hematologic malignancies.
DOI: 10.2183/pjab.102.005
Institution: The University of Osaka
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Funders: Naito Foundation, Takeda Science Foundation, Cell Science Research Foundation, Sumitomo Foundation, Japan Research Foundation for Clinical Pharmacology, Uehara Memorial Foundation, Japan Agency for Medical Research and Development, Naito Science and Engineering Foundation, Friends of Leukemia Research Fund, Japanese Society of Hematology, Japan Medical Association, Mitsubishi Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Kobayashi Foundation for Cancer Research, Princess Takamatsu Cancer Research Fund, Ono Pharmaceutical, MSD Life Science Foundation, Public Interest Incorporated Foundation, Japan Society for the Promotion of Science, Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Chemo-Sero-Therapeutic Research Institute
Awards: G2144358466, G2576085165, G2839194946, 転写後制御機構の観点からみる造血異常と治療応用, G3577919232, 新次元の単一細胞解析が駆動する骨髄造血系の統合的理解, G4258973613, Studies of MDS pathogenesis and its relation to novel therapeutic strategies, G5493902635, G5626572802, G6560137190, BRD9スプライシング異常との合成致死性を利用した新規治療戦略の開発, G6718509927, Innovation of the novel therapeutic strategies against p53 mutated acute myeloid leukemia., 造血幹細胞を中心とした多細胞間の適応・修復ネットワークの解明と制御
OpenAlex ID: W7128544094