1. Oncogenic dependency on SWI/SNF chromatin remodeling factors in T-cell acute lymphoblastic leukemia.
- Author
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Kim H, Tan TK, Lee DZY, Huang XZ, Ong JZL, Kelliher MA, Yeoh AEJ, Sanda T, and Tan SH
- Subjects
- Humans, Chromosomal Proteins, Non-Histone metabolism, Chromosomal Proteins, Non-Histone genetics, Receptor, Notch1 metabolism, Receptor, Notch1 genetics, Core Binding Factor Alpha 2 Subunit genetics, Core Binding Factor Alpha 2 Subunit metabolism, Apoptosis, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins c-myc genetics, Gene Expression Regulation, Leukemic, Cell Line, Tumor, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma etiology, Transcription Factors metabolism, Transcription Factors genetics, Chromatin Assembly and Disassembly, Nuclear Proteins metabolism, Nuclear Proteins genetics, DNA Helicases genetics, DNA Helicases metabolism
- 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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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