SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia

Molecular Cancer Research : MCR
Shankha Subhra ChatterjeeAmitava Sengupta

Abstract

SWI/SNF is an evolutionarily conserved multi-subunit chromatin remodeling complex that regulates epigenetic architecture and cellular identity. Although SWI/SNF genes are altered in approximately 25% of human malignancies, evidences showing their involvement in tumor cell-autonomous chromatin regulation and transcriptional plasticity are limiting. This study demonstrates that human primary acute myeloid leukemia (AML) cells exhibit near complete loss of SMARCB1 (BAF47 or SNF5/INI1) and SMARCD2 (BAF60B) associated with nucleation of SWI/SNFΔ SMARCC1 (BAF155), an intact core component of SWI/SNFΔ, colocalized with H3K27Ac to target oncogenic loci in primary AML cells. Interestingly, gene ontology (GO) term and pathway analysis suggested that SMARCC1 occupancy was enriched on genes regulating Rac GTPase activation, cell trafficking, and AML-associated transcriptional dysregulation. Transcriptome profiling revealed that expression of these genes is upregulated in primary AML blasts, and loss-of-function studies confirmed transcriptional regulation of Rac GTPase guanine nucleotide exchange factors (GEF) by SMARCB1. Mechanistically, loss of SMARCB1 increased recruitment of SWI/SNFΔ and associated histone acetyltransferases (HAT) to t...Continue Reading

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Citations

Jan 23, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mayukh BiswasAmitava Sengupta
May 31, 2020·BMC Bioinformatics·Elisabetta SautaRiccardo Bellazzi
Apr 16, 2019·Expert Review of Anticancer Therapy·Krystal A OrlandoBernard E Weissman
Dec 19, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sayan ChakrabortyAmitava Sengupta
Jul 13, 2021·Frontiers in Cell and Developmental Biology·Zhao-Ming XiaoShan-Chao Zhao
May 1, 2021·Annual Review of Genomics and Human Genetics·Bernd B Zeisig, Chi Wai Eric So
Sep 27, 2020·Journal of Hematology & Oncology·Junqing WuGuoji Guo

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