Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions

• Published in: Blood cancer discovery Vol. 1; no. 1; pp. 48 - 67
• Main Authors: Silvestri, Giovannino, Trotta, Rossana, Stramucci, Lorenzo, Ellis, Justin J, Harb, Jason G, Neviani, Paolo, Wang, Shuzhen, Eisfeld, Ann-Kathrin, Walker, Christopher J, Zhang, Bin, Srutova, Klara, Gambacorti-Passerini, Carlo, Pineda, Gabriel, Jamieson, Catriona H M, Stagno, Fabio, Vigneri, Paolo, Nteliopoulos, Georgios, May, Philippa C, Reid, Alistair G, Garzon, Ramiro, Roy, Denis-Claude, Moutuou, Moutuaata M, Guimond, Martin, Hokland, Peter, Deininger, Michael W, Fitzgerald, Garrett, Harman, Christopher, Dazzi, Francesco, Milojkovic, Dragana, Apperley, Jane F, Marcucci, Guido, Qi, Jianfei, Polakova, Katerina Machova, Zou, Ying, Fan, Xiaoxuan, Baer, Maria R, Calabretta, Bruno, Perrotti, Danilo
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-07-2020
• Subjects: Humans; Killer Cells, Natural; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; MicroRNAs - genetics; Neoplastic Stem Cells; Protein Kinase Inhibitors - metabolism; Protein Phosphatase 2 - genetics; Tumor Microenvironment - genetics
• ISSN: 2643-3230; 2643-3249
• DOI: 10.1158/0008-5472.BCD-19-0039

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
has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively.
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
in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating
long noncoding RNA that uncouples and limits
function to cytostasis. Genetic and pharmacologic
modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis
and in patient-derived xenografts; hence, the importance of
and PP2A activity for CML development and therapy.