miRNA-Mediated Rescue of NK Cell Cytotoxicity Against Drug-Resistant Quiescent Leukemia Stem Cells
Abstract
Qualitative and quantitative defects in natural killer (NK) cells is a feature contribute to survival of BCR-ABL1 tyrosine kinase inhibitor (TKI)-resistant quiescent leukemia-initiating stem cells (qLSCs) in TKI-treated chronic myelogenous leukemia (CML) patients. The goal of this project was to determine whether miR-155 expression confers to NK cells the ability to overcome the BM mesenchymal stem cell (MSC) and hypoxia-induced inhibitory effects on their proliferation and anti-cancer cytotoxicity, and efficiently kill TKI-resistant CML qLSCs. We found that expression of pre-miR-155 but not mature miR-155 markedly and significantly increased absolute numbers of BM NK cells and their cytotoxic activity against leukemic but not normal quiescent (CFSEmax) LSCs. Moreover, we found that BM-induced NK cell inhibition was dependent on increased miR-300. Mechanistically we found that pre-miR-155activity was dependent on increased SET and SHIP1 inhibition, and on FAS and DR5 expression, which would make CML qLSCs more susceptible to NK cell killing.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1205003
Entities
People
- Danilo Perrotti
- Rossana Trotta
Organizations
- University of Maryland, Baltimore