| Literature DB >> 32885175 |
Robert J Autry1,2,3, Steven W Paugh1,2, Robert Carter4,5, Lei Shi6, Jingjing Liu5, Daniel C Ferguson1,2, Calvin E Lau1,2,7, Erik J Bonten1,2, Wenjian Yang1,2, J Robert McCorkle1,2, Jordan A Beard1,2, John C Panetta2, Jonathan D Diedrich1,2, Kristine R Crews1,2, Deqing Pei6, Christopher J Coke1,2, Sivaraman Natarajan4,5, Alireza Khatamian5, Seth E Karol1,4,8, Elixabet Lopez-Lopez1,2, Barthelemy Diouf1,2, Colton Smith1,2, Yoshihiro Gocho1,2, Kohei Hagiwara5, Kathryn G Roberts1,9, Stanley Pounds6, Steven M Kornblau10, Wendy Stock11, Elisabeth M Paietta12, Mark R Litzow13, Hiroto Inaba1,4, Charles G Mullighan1,4,9, Sima Jeha1,4,9, Ching-Hon Pui1,4,9, Cheng Cheng6, Daniel Savic1,2, Jiyang Yu5, Charles Gawad4,5, Mary V Relling1,2,3, Jun J Yang1,2,4, William E Evans14,15,16.
Abstract
Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of mRNA and miRNA expression, DNA methylation, SNPs, CNAs and SNVs/Indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid-resistance. Single cell RNAseq and network-based transcriptomic modelling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells.Entities:
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Year: 2020 PMID： 32885175 PMCID： PMC7467080 DOI： 10.1038/s43018-020-0037-3
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347