Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia

Robert J. Autry, Steven W. Paugh, Robert Carter, Lei Shi, Jingjing Liu, Daniel C. Ferguson, Calvin E. Lau, Erik J. Bonten, Wenjian Yang, J. Robert McCorkle, Jordan A. Beard, John C. Panetta, Jonathan D. Diedrich, Kristine R. Crews, Deqing Pei, Christopher J. Coke, Sivaraman Natarajan, Alireza Khatamian, Seth E. Karol, Elixabet Lopez-LopezBarthelemy Diouf, Colton Smith, Yoshihiro Gocho, Kohei Hagiwara, Kathryn G. Roberts, Stanley Pounds, Steven M. Kornblau, Wendy Stock, Elisabeth M. Paietta, Mark R. Litzow, Hiroto Inaba, Charles G. Mullighan, Sima Jeha, Ching Hon Pui, Cheng Cheng, Daniel Savic, Jiyang Yu, Charles Gawad, Mary V. Relling, Jun J. Yang, William E. Evans

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)329-344
Number of pages16
JournalNature Cancer
Volume1
Issue number3
DOIs
StatePublished - Mar 1 2020

ASJC Scopus subject areas

  • Medicine(all)

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