The miR-185/PAK6 axis predicts therapy response and regulates ..

MYELOID NEOPLASIA| JULY 30, 2020

The miR-185/PAK6 axis predicts therapy response and regulates survival of drug-resistant leukemic stem cells in CML

Hanyang Lin, Katharina Rothe, Min Chen, Andrew Wu, Artem Babaian, Ryan Yen, Jonathan Zeng, Jens Ruschmann, Oleh I. Petriv, Kieran O'Neill, Tobias Maetzig, David J. H. F. Knapp, Naoto Nakamichi, Ryan Brinkman, Inanc Birol, Donna L. Forrest, Carl Hansen, R. Keith Humphries, Connie J. Eaves, Xiaoyan Jiang

Blood (2020) 136 (5): 596–609.

https://doi.org/10.1182/blood.2019003636

Key Points

miR-185 is discovered to predict therapy response in treatment-naive patients with CML, and functions as a tumor suppressor.

Its restored expression impairs LSC survival, sensitizing them to therapy; PAK6 is a target gene of miR-185, mediating drug resistance.

Abstract

Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of microRNAs (miRNAs) in regulating drug resistance 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 xenotransplantation 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.

Subjects:

Myeloid Neoplasia

Topics:

leukemic hematopoietic stem cell, micrornas, protein-tyrosine kinase inhibitor, leukemia, myelocytic, chronic, stem cells, biological markers, therapy naive, transplantation, heterologous

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