Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions
Abstract
Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that MIR300 has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. MIR300 is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates MIR300 in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating TUG1 long noncoding RNA that uncouples and limits MIR300 function to cytostasis. Genetic and pharmacologic MIR300 modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis in vitro and in patient-derived xenografts; hence, the importance of MIR300 and PP2A activity for CML development and therapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 04, 2020
- Source ID
- 10.1158/0008-5472.bcd-19-0039
Entities
People
- Alistair G. Reid
- Ann-kathrin Eisfeld
- Bin Zhang
- Bruno Calabretta
- Carlo Gambacorti-passerini
- Catriona H. M. Jamieson
- Christopher Harman
- Christopher J. Walker
- Danilo Perrotti
- Denis-claude Roy
- Dragana Milojkovic
- Fabio Stagno
- Francesco Dazzi
- Gabriel Pineda
- Garrett Fitzgerald
- Georgios Nteliopoulos
- Giovannino Silvestri
- Guido Marcucci
- Jane F. Apperley
- Jason G. Harb
- Jianfei Qi
- Justin J. Ellis
- Katerina Machova Polakova
- Klara Srutova
- Lorenzo Stramucci
- Maria R. Baer
- Martin Guimond
- Michael W. Deininger
- Moutuaata M. Moutuou
- Paolo Neviani
- Paolo Vigneri
- Peter Hokland
- Philippa C. May
- Ramiro Garzon
- Rossana Trotta
- Shuzhen Wang
- Xiaoxuan Fan
- Ying Zou
Organizations
- Aarhus University Hospital
- American Cryonics Society
- Cancer Research Society
- Charles University
- City of Hope National Medical Center
- Imperial College London
- King's College London
- National Institutes of Health
- National Natural Science Foundation of China
- National University
- Ohio State University
- Thomas Jefferson University
- United States Department of Defense
- University of California, San Diego
- University of Catania
- University of Maryland School of Medicine
- University of Utah
- Université de Montréal