Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia
Abstract
The unfolded protein response (UPR) mitigates endoplasmic reticulum (ER) stress. In this regard, ER stress-inducing agents were found to be highly active in a clinical trial for children with relapsed acute lymphoblastic leukemia (ALL), a disease derived from transformed pre-B cells. To understand the efficacy of ER stress-inducing agents in pre-B ALL, we studied the relevance of the UPR pathway in genetic and patient-derived (xenograft) models of human pre-B ALL. Our studies revealed an unrecognized vulnerability of both normal pre-B cells and pre-B cell-derived ALL cells to genetic or pharmacological blockade of the UPR pathway. Our results establish a mechanistic rationale for the treatment of children with pre-B ALL with agents that block the UPR pathway and induce ER stress.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- May 2014
- DOI:
- 10.1073/pnas.1400958111
- Bibcode:
- 2014PNAS..111E2219K