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

dc.contributor.authorAutry, R. J.
dc.contributor.authorPaugh, S. W.
dc.contributor.authorCarter, R.
dc.contributor.authorShi, L.
dc.contributor.authorLiu, J.
dc.contributor.authorFerguson, D.
dc.contributor.authorLau, C. E.
dc.contributor.authorBonten, E. J.
dc.contributor.authorYang, W.
dc.contributor.authorMcCorkle, J. R.
dc.contributor.authorBeard, J. A.
dc.contributor.authorPanetta, J. C.
dc.contributor.authorDiedrich, J.
dc.contributor.authorCrews, K..R.
dc.contributor.authorPei, D.
dc.contributor.authorCoke, C. J.
dc.contributor.authorNatarajan, S.
dc.contributor.authorKhatamian, A.
dc.contributor.authorKarol, S. E.
dc.contributor.authorLópez López, Elixabet ORCID
dc.contributor.authorDiouf, B.
dc.contributor.authorSmith, C.
dc.contributor.authorGocho, Y.
dc.contributor.authorHagiwara, K.
dc.contributor.authorRoberts, K. G.
dc.contributor.authorPounds, S.
dc.contributor.authorKornblau, S. M.
dc.contributor.authorStock, W.
dc.contributor.authorPaietta, E. M.
dc.contributor.authorLitzow, M. R.
dc.contributor.authorInaba, H.
dc.date.accessioned2024-04-29T18:25:00Z
dc.date.available2024-04-29T18:25:00Z
dc.date.issued2020-03
dc.identifier.citationNature Cancer 1(3) : 329-34 (2020)es_ES
dc.identifier.issn2662-1347
dc.identifier.urihttp://hdl.handle.net/10810/66935
dc.description.abstractIdentification 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.es_ES
dc.description.sponsorshipResearch reported in this publication was supported in part by funds from the NIH (grant nos. R01 CA36401 (to W.E.E.), P50 GM115279 (to M.V.R., J.J.Y., C.G.M. and W.E.E.), U01 GM92666 (to M.V.R. and W.E.E.)), a St. Jude Comprehensive Cancer Center grant (no. CA21765) from the National Cancer Institute, and the American Lebanese Syrian Associated Charitieses_ES
dc.language.isoenges_ES
dc.publisherSpringer Naturees_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.titleIntegrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemiaes_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holder© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.es_ES
dc.relation.publisherversionhttps://www.nature.com/articles/s43018-020-0037-3es_ES
dc.identifier.doi10.1038/s43018-020-0037-3
dc.departamentoesGenética, antropología física y fisiología animales_ES
dc.departamentoeuGenetika,antropologia fisikoa eta animalien fisiologiaes_ES


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