Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia
- 9 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (3), 329-344
- https://doi.org/10.1038/s43018-020-0037-3
Abstract
Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of messenger RNA and microRNA (miRNA) expression, DNA methylation, single-nucleotide polymorphisms, copy number alterations and single-nucleotide variants/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 RNA-sequencing and network-based transcriptomic modeling 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.Keywords
Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (P50 GM115279, U01 GM92666)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA21765)
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