TitleSuppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia.
Publication TypeJournal Article
Year of Publication2017
AuthorsKruth KA, Fang M, Shelton DN, Abu-Halawa O, Mahling R, Yang H, Weissman JS, Loh ML, Müschen M, Tasian SK, Bassik MC, Kampmann M, Pufall MA
Date Published2017 06 01
KeywordsCell Death, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases, Dexamethasone, Drug Resistance, Neoplasm, Gene Expression Regulation, Glucocorticoids, Humans, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cells, B-Lymphoid, Proto-Oncogene Proteins c-bcr, Receptors, Glucocorticoid, RNA, Small Interfering, Signal Transduction

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.

Alternate JournalBlood
PubMed ID28424165
PubMed Central IDPMC5454339
Grant ListR00 CA149088 / CA / NCI NIH HHS / United States
K99 CA181494 / CA / NCI NIH HHS / United States
R00 CA181494 / CA / NCI NIH HHS / United States
K08 CA184418 / CA / NCI NIH HHS / United States
P30 CA086862 / CA / NCI NIH HHS / United States
R01 CA213138 / CA / NCI NIH HHS / United States
R01 CA157644 / CA / NCI NIH HHS / United States
R35 CA197628 / CA / NCI NIH HHS / United States
K99 CA149088 / CA / NCI NIH HHS / United States