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-Lopez; Barthelemy 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

doi:10.1038/s43018-020-0037-3

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

Oncology

Research output: Contribution to journal › Article › peer-review

37 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 language	English (US)
Pages (from-to)	329-344
Number of pages	16
Journal	Nature Cancer
Volume	1
Issue number	3
DOIs	https://doi.org/10.1038/s43018-020-0037-3
State	Published - Mar 1 2020

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s43018-020-0037-3

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Autry, R. J., Paugh, S. W., Carter, R., Shi, L., Liu, J., Ferguson, D. C., Lau, C. E., Bonten, E. J., Yang, W., McCorkle, J. R., Beard, J. A., Panetta, J. C., Diedrich, J. D., Crews, K. R., Pei, D., Coke, C. J., Natarajan, S., Khatamian, A., Karol, S. E., ... Evans, W. E. (2020). Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia. Nature Cancer, 1(3), 329-344. https://doi.org/10.1038/s43018-020-0037-3

Autry, RJ, Paugh, SW, Carter, R, Shi, L, Liu, J, Ferguson, DC, Lau, CE, Bonten, EJ, Yang, W, McCorkle, JR, Beard, JA, Panetta, JC, Diedrich, JD, Crews, KR, Pei, D, Coke, CJ, Natarajan, S, Khatamian, A, Karol, SE, Lopez-Lopez, E, Diouf, B, Smith, C, Gocho, Y, Hagiwara, K, Roberts, KG, Pounds, S, Kornblau, SM, Stock, W, Paietta, EM, Litzow, MR, Inaba, H, Mullighan, CG, Jeha, S, Pui, CH, Cheng, C, Savic, D, Yu, J, Gawad, C, Relling, MV, Yang, JJ & Evans, WE 2020, 'Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia', Nature Cancer, vol. 1, no. 3, pp. 329-344. https://doi.org/10.1038/s43018-020-0037-3

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title = "Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia",

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.",

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

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doi = "10.1038/s43018-020-0037-3",

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T1 - Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia

AU - Autry, Robert J.

AU - Paugh, Steven W.

AU - Carter, Robert

AU - Shi, Lei

AU - Liu, Jingjing

AU - Ferguson, Daniel C.

AU - Lau, Calvin E.

AU - Bonten, Erik J.

AU - Yang, Wenjian

AU - McCorkle, J. Robert

AU - Beard, Jordan A.

AU - Panetta, John C.

AU - Diedrich, Jonathan D.

AU - Crews, Kristine R.

AU - Pei, Deqing

AU - Coke, Christopher J.

AU - Natarajan, Sivaraman

AU - Khatamian, Alireza

AU - Karol, Seth E.

AU - Lopez-Lopez, Elixabet

AU - Diouf, Barthelemy

AU - Smith, Colton

AU - Gocho, Yoshihiro

AU - Hagiwara, Kohei

AU - Roberts, Kathryn G.

AU - Pounds, Stanley

AU - Kornblau, Steven M.

AU - Stock, Wendy

AU - Paietta, Elisabeth M.

AU - Litzow, Mark R.

AU - Inaba, Hiroto

AU - Mullighan, Charles G.

AU - Jeha, Sima

AU - Pui, Ching Hon

AU - Cheng, Cheng

AU - Savic, Daniel

AU - Yu, Jiyang

AU - Gawad, Charles

AU - Relling, Mary V.

AU - Yang, Jun J.

AU - Evans, William E.

PY - 2020/3/1

Y1 - 2020/3/1

N2 - 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.

AB - 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.

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AN - SCOPUS:85097255614

SN - 2662-1347

VL - 1

SP - 329

EP - 344

JO - Nature Cancer

JF - Nature Cancer

IS - 3

ER -

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

Abstract

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