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

Karina 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

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

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


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 glucocorticoid 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 shRNA 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 PI3Kδ, a lynchpin in the pre-B-cell receptor and IL7R 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 2, 2017.
  • Accepted March 29, 2017.