Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia

Karina A Kruth; Mimi Fang; Dawne N Shelton; Ossama Abu-Halawa; Ryan Mahling; Hongxing Yang; Jonathan S Weissman; Mignon L Loh; Markus Müschen; Sarah K Tasian; Michael C Bassik; Martin Kampmann; Miles A Pufall

doi:10.1182/blood-2017-02-766204

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Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia

Journal article

Open access

Peer reviewed

Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia

Karina A Kruth, Mimi Fang, Dawne N Shelton, Ossama Abu-Halawa, Ryan Mahling, Hongxing Yang, Jonathan S Weissman, Mignon L Loh, Markus Müschen, Sarah K Tasian, …

Blood, Vol.129(22), pp.3000-3008

06/01/2017

DOI: 10.1182/blood-2017-02-766204

PMCID: PMC5454339

PMID: 28424165

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Abstract

Glucocorticoids (GCs), including dexamethasone (dex), are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the GC receptor (GR), a ligand-induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, which pathways affect their regulation, and how resistance arises are not well understood. Here, we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation short hairpin RNA screen to identify GC-regulated "effector" genes that contribute to cell death, as well as genes that affect the sensitivity of B-ALL cells to dex. This analysis reveals a pervasive role for GCs in suppression of B-cell development genes that is linked to therapeutic response. Inhibition of phosphatidylinositol 3-kinase δ (PI3Kδ), a linchpin in the pre-B-cell receptor and interleukin 7 receptor signaling pathways critical to B-cell development (with CAL-101 [idelalisib]), interrupts a double-negative feedback loop, enhancing GC-regulated transcription to synergistically kill even highly resistant B-ALL with diverse genetic backgrounds. This work not only identifies numerous opportunities for enhanced lymphoid-specific combination chemotherapies that have the potential to overcome treatment resistance, but is also a valuable resource for understanding GC biology and the mechanistic details of GR-regulated transcription.

RNA, Small Interfering - genetics

Glucocorticoids - therapeutic use

Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology

Proto-Oncogene Proteins c-bcr - metabolism

Class I Phosphatidylinositol 3-Kinases - genetics

Class I Phosphatidylinositol 3-Kinases - metabolism

Signal Transduction

Humans

Precursor Cells, B-Lymphoid - metabolism

Precursor Cells, B-Lymphoid - drug effects

Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors

Gene Expression Regulation - drug effects

Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics

Drug Resistance, Neoplasm - genetics

Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy

Dexamethasone - pharmacology

Cell Death - genetics

Precursor Cells, B-Lymphoid - pathology

Proto-Oncogene Proteins c-bcr - genetics

Cell Line, Tumor

Cell Death - drug effects

Receptors, Glucocorticoid - drug effects

Details

Title: Subtitle: Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia
Creators: Karina A Kruth - Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA
Mimi Fang - Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA
Dawne N Shelton - Bio-Rad Laboratories, Hercules, CA
Ossama Abu-Halawa - Coe College, Cedar Rapids, IA
Ryan Mahling - Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA
Hongxing Yang - Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA
Jonathan S Weissman - Howard Hughes Medical Institute, Chevy Chase, MD
Mignon L Loh - Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA
Markus Müschen - Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA
Sarah K Tasian - Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Michael C Bassik - Department of Genetics, School of Medicine, Stanford University, Stanford, CA; and
Martin Kampmann - Chan-Zuckerberg Biohub, UCSF, San Francisco, CA
Miles A Pufall - Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA
Resource Type: Journal article
Publication Details: Blood, Vol.129(22), pp.3000-3008
Publisher: United States
DOI: 10.1182/blood-2017-02-766204
PMID: 28424165
PMCID: PMC5454339
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: R00 CA149088 / NCI NIH HHS R00 CA181494 / NCI NIH HHS K99 CA149088 / NCI NIH HHS K99 CA181494 / NCI NIH HHS K08 CA184418 / NCI NIH HHS R01 CA157644 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 06/01/2017
Academic Unit: Psychiatry; Biochemistry and Molecular Biology
Record Identifier: 9984024513402771

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