Affiliations
- 1Cancer Science Institute of Singapore, National University of, Singapore, 117599, Singapore.
- 2Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
- 3Department of Pediatrics, National University of, Singapore, Singapore.
- 4Cancer Science Institute of Singapore, National University of, Singapore, 117599, Singapore. Takaomi_Sanda@u.nus.edu.
- 5Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore. Takaomi_Sanda@u.nus.edu.
- 6Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan. Takaomi_Sanda@u.nus.edu.
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy arising from immature thymocytes. Unlike well-known oncogenic transcription factors, such as NOTCH1 and MYC, the involvement of chromatin remodeling factors in T-ALL pathogenesis is poorly understood. Here, we provide compelling evidence on how SWI/SNF chromatin remodeling complex contributes to human T-ALL pathogenesis. Integrative analysis of transcriptomic and ATAC-Seq datasets revealed high expression of SMARCA4, one of the subunits of the SWI/SNF complex, in T-ALL patient samples and cell lines compared to normal T cells. Loss of SMARCA protein function resulted in apoptosis induction and growth inhibition in multiple T-ALL cell lines. ATAC-Seq analysis revealed a massive reduction in chromatin accessibility across the genome after the loss of SMARCA protein function. RUNX1 interacts with SMARCA4 protein and co-occupies the same genomic regions. Importantly, the NOTCH1-MYC pathway was primarily affected when SMARCA protein function was impaired, implicating SWI/SNF as a novel therapeutic target.
- PMID: 38969731 DOI: 10.1038/s41375-024-02331-6