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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 and Miles A. Pufall

Key Points

  • Next-generation functional genomics identifies B-cell development genes, pathways, and feedback loops that affect dex activity in B-ALL.

  • Suppression of lymphoid-restricted PI3Kδ synergizes with dex in B-ALL by enhancing or restoring regulation of cell-death genes.

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.

  • Submitted February 1, 2017.
  • Accepted March 29, 2017.
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