Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia.
Karina A KruthMimi FangDawne N SheltonOssama Abu-HalawaRyan MahlingHongxing YangJonathan S WeissmanMignon L LohMarkus MüschenSarah K TasianMichael C BassikMartin Edward KampmannMiles A PufallPublished in: Blood (2017)
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.
Keyphrases
- transcription factor
- genome wide identification
- genome wide
- acute lymphoblastic leukemia
- cell death
- bioinformatics analysis
- signaling pathway
- cell cycle arrest
- dna binding
- dna methylation
- gas chromatography
- induced apoptosis
- gene expression
- genome wide analysis
- allogeneic hematopoietic stem cell transplantation
- oxidative stress
- diabetic rats
- epithelial mesenchymal transition
- endothelial cells
- cell proliferation
- copy number
- combination therapy
- risk assessment
- mass spectrometry
- pi k akt
- high glucose
- tyrosine kinase
- early life
- high resolution