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Publications of the Week

The miR-185/PAK6 Axis Predicts Therapy Response and Regulates Survival of Drug-Resistant Leukemic Stem Cells in CML

By April 30, 2020No Comments

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This week we profile a recent publication in Blood from Dr. Leon Lin (pictured) in the laboratory of Dr. Xiaoyan Jiang at BC Cancer.

Can you provide a brief overview of your lab’s current research focus?

The current research focus of our lab is to understand the molecular mechanisms and cellular functions of specific oncogenes, tumour suppressor genes, miRNAs/target genes in human leukemia in order to develop mechanism-based combination therapeutic strategies that can directly target drug-insensitive leukemic stem cells (LSCs), leading to curative therapies for leukemia patients.

What is the significance of the findings in this publication?

In this study, we performed global transcriptome profiling in leukemic stem/progenitor cells from treatment-naive chronic myeloid leukemia (CML) patients, and identified miR-185 as one of the most deregulated miRNAs. We were able to characterize miR-185 as a tumour suppressor, for its restored expression sensitized drug-resistant cells to tyrosine kinase inhibitors (TKIs) in vitro, and eliminated long-term repopulating LSCs and infiltrating blast cells in vivo. We also uncovered, for the first time, PAK6 to be a crucial target of miR-185, and pharmacological inhibition of PAK6 sensitized therapy-resistant cells to TKIs by perturbing their RAS/MAPK and mitochondrial activity. Together our data indicated that miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL may provide a valuable strategy for overcoming drug resistance in CML patients.

What are the next steps for this research?

Based on the random forest algorithm trained on our data set, miR-185 was implicated as a biomarker predictive of TKI responsiveness in treatment-naive CML patient cells. We are currently in discussion with our clinical collaborators and industry partners to obtain large cohorts of CML patient samples to further test the predictive power of miR-185. In addition, since PAK6 plays a role in the development of chemoresistance in solid tumours, we will investigate the effects of PAK inhibition in other hematological diseases that are notoriously resistant to chemotherapies.

This work was funded by:

If you’d like us to mention your funding sources, please list them.
This work was supported by the Canadian Cancer Society, the Leukemia & Lymphoma Society of Canada, the Canadian Institutes of Health Research, the Cancer Research Society and Novartis Canada.

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