Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 10, Issue 427, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aan8735
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Funding
- Canadian Institutes of Health Research
- Canadian Cancer Society
- Leukemia & Lymphoma Society of Canada
- Cancer Research Society
- MITACS postdoctoral fellowships
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Overcoming drug resistance and targeting leukemic stem cells (LSCs) remain major challenges in curing BCR-ABL(+) human leukemia. Using an advanced drug/proliferation screen, we have uncovered a prosurvival role for protein phosphatase 2A (PP2A) in tyrosine kinase inhibitor (TKI)-insensitive leukemic cells, regulated by an Abelson helper integration site-1-mediated PP2A-beta-catenin-BCR-ABL-JAK2 protein complex. Genetic and pharmacological inhibition of PP2A impairs survival of TKI nonresponder cells and sensitizes them to TKIs in vitro, inducing a dramatic loss of several key proteins, including beta-catenin. We also demonstrate that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, selectively eliminate treatment-naive TKI-insensitive stem and progenitor cells, while sparing healthy counterparts. In addition, PP2A inhibitors and TKIs act synergistically to inhibit the growth of TKI-insensitive cells, as assessed by combination index analysis. The combination eliminates infiltrated BCR-ABL+ blast cells and drug-insensitive LSCs and confers a survival advantage in preclinical xenotransplant models. Thus, dual PP2A and BCR-ABL inhibition may be a valuable therapeutic strategy to synergistically target drug-insensitive LSCs that maintain minimal residual disease in patients.
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