ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine Journal Article

   

Authors:	Rahmani, N. E.; Ramachandra, N.; Sahu, S.; Gitego, N.; Lopez, A.; Pradhan, K.; Bhagat, T. D.; Gordon-Mitchell, S.; Pena, B. R.; Kazemi, M.; Rao, K.; Giricz, O.; Maqbool, S. B.; Olea, R.; Zhao, Y.; Zhang, J.; Dolatshad, H.; Tittrea, V.; Tatwavedi, D.; Singh, S.; Lee, J.; Sun, T.; Steidl, U.; Shastri, A.; Inoue, D.; Abdel-Wahab, O.; Pellagatti, A.; Gavathiotis, E.; Boultwood, J.; Verma, A.
Article Title:	ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine
Abstract:	The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation. © 2021, The Author(s).
Journal Title:	Blood Cancer Journal
Volume:	11
Issue:	9
ISSN:	2044-5385
Publisher:	Nature Publishing Group
Date Published:	2021-09-21
Start Page:	157
Language:	English
DOI:	10.1038/s41408-021-00541-0
PROVIDER:	scopus
PUBMED:	34548471
PMCID:	PMC8455571
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85115378677&doi=10.1038%2fs41408-021-00541-0&partnerID=40&md5=67f2f5c09765ec4b3e6ef0ed067ec783
Notes:	Article -- Export Date: 1 October 2021 -- Source: Scopus

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