Journal
BLOOD
Volume 136, Issue 5, Pages 596-609Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019003636
Keywords
-
Categories
Funding
- Canadian Cancer Society [705148]
- Leukemia & Lymphoma Society of Canada
- Canadian Institutes of Health Research (CIHR) [427201]
- Cancer Research Society
- CIHR Frederick Banting and Charles Best Canada Graduate Scholarship
- Mathematics of Information Technology and Complex Systems (MITACS) Elevate postdoctoral fellowship
- Roman M. Babicki Fellowship in Medical Research from the University of British Columbia (UBC)
- Four-Year Fellowship from UBC
- CIHR Frederick Banting
- Charles Best Canada Graduate Scholarship
Ask authors/readers for more resources
Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of microRNAs (miRNAs) in regulating drug re-sistance and leukemic stem cell (LSC) fate, we performed global transcriptome profiling in treatment-naive chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor: its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in preclinical xeno-transplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185, and pharmacological inhibition of PAK6 perturbed the RAS/ MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL1 may provide a valuable strategy for overcoming drug resistance in patients.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available