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

Animals Drug Resistance, Neoplasm / genetics Genomics Glucocorticoids / pharmacology Humans Mice MicroRNAs / genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy

Journal

Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119

Informations de publication

Date de publication:
03 2020
Historique:
entrez: 5 9 2020
pubmed: 5 9 2020
medline: 5 9 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s43018-020-0037-3 PMID: 32885175 PMC: PMC7467080
pubmed: 32885175
doi: 10.1038/s43018-020-0037-3
pmc: PMC7467080
mid: NIHMS1614339
pii: 10.1038/s43018-020-0037-3
doi:

Substances chimiques

Glucocorticoids 0
MicroRNAs 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Pagination

329-344

Subventions

Organisme : NCI NIH HHS
ID : R25 CA023944
Pays : United States
Organisme : NCI NIH HHS
ID : DP2 CA239145
Pays : United States
Organisme : NCI NIH HHS
ID : L40 CA162153
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA036401
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180820
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM115279
Pays : United States

Déclaration de conflit d'intérêts

Competing Interests The authors declare no competing interests.

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Auteurs

Robert J Autry (RJ)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA.
ORCID: 0000-0002-6965-2942

Steven W Paugh (SW)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Robert Carter (R)

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Lei Shi (L)

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.

Jingjing Liu (J)

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
ORCID: 0000-0002-8184-8382

Daniel C Ferguson (DC)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Calvin E Lau (CE)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Pediatric Oncology Education Program, St. Jude Children's Research Hospital, Memphis, TN, USA.

Erik J Bonten (EJ)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Wenjian Yang (W)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

J Robert McCorkle (JR)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Jordan A Beard (JA)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

John C Panetta (JC)

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Jonathan D Diedrich (JD)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Kristine R Crews (KR)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Deqing Pei (D)

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.

Christopher J Coke (CJ)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Sivaraman Natarajan (S)

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Alireza Khatamian (A)

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Seth E Karol (SE)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, TN, USA.
ORCID: 0000-0001-8113-8180

Elixabet Lopez-Lopez (E)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Barthelemy Diouf (B)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
ORCID: 0000-0002-3947-0611

Colton Smith (C)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Yoshihiro Gocho (Y)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Kohei Hagiwara (K)

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Kathryn G Roberts (KG)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Stanley Pounds (S)

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
ORCID: 0000-0002-9167-2114

Steven M Kornblau (SM)

Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
ORCID: 0000-0002-5990-9548

Wendy Stock (W)

Hematopoiesis and Hematological Malignancies Program, University of Chicago, Chicago, IL, USA.

Elisabeth M Paietta (EM)

Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, North Division, Bronx, NY, USA.

Mark R Litzow (MR)

Division of Hematology and Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Hiroto Inaba (H)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Charles G Mullighan (CG)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
ORCID: 0000-0002-1871-1850

Sima Jeha (S)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Ching-Hon Pui (CH)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
ORCID: 0000-0003-0303-5658

Cheng Cheng (C)

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.

Daniel Savic (D)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Jiyang Yu (J)

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Charles Gawad (C)

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Mary V Relling (MV)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA.

Jun J Yang (JJ)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
ORCID: 0000-0002-0770-9659

William E Evans (WE)

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN, USA. William.Evans@stjude.org.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. William.Evans@stjude.org.
Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA. William.Evans@stjude.org.
ORCID: 0000-0002-9333-5322

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