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Blood. 2017 Jun 1;129(22):3000-3008. doi: 10.1182/blood-2017-02-766204. Epub 2017 Apr 19.

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

Author information

1
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA.
2
Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA.
3
Bio-Rad Laboratories, Hercules, CA.
4
Coe College, Cedar Rapids, IA.
5
Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), San Francisco, CA.
6
Howard Hughes Medical Institute, Chevy Chase, MD.
7
Department of Pediatrics, Benioff Children's Hospital and.
8
Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA.
9
Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
10
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
11
Department of Genetics, School of Medicine, Stanford University, Stanford, CA; and.
12
Department of Biochemistry and Biophysics.
13
Institute for Neurodegenerative Diseases, and.
14
Chan-Zuckerberg Biohub, UCSF, San Francisco, CA.

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.

PMID:
28424165
PMCID:
PMC5454339
DOI:
10.1182/blood-2017-02-766204
[Indexed for MEDLINE]
Free PMC Article

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