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

Abstract

<h3></h3> 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 <i>MIR300</i> has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. <i>MIR300</i> 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 <i>MIR300</i> in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating <i>TUG1</i> long noncoding RNA that uncouples and limits <i>MIR300</i> function to cytostasis. Genetic and pharmacologic <i>MIR300</i> modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis <i>in vitro</i> and in patient-derived xenografts; hence, the importance of <i>MIR300</i> and PP2A activity for CML development and therapy. <h3>Significance:</h3> Tumor-naïve microenvironment–induced <i>MIR300</i> is the only tumor suppressor miRNA that induces CML LSC quiescence while inhibiting NK cell antitumor immune response, and CML LSC/progenitor cell apoptosis through its anti-proliferative and PP2A-activating functions, respectively. Thus, the importance of <i>MIR300</i> and PP2A-activating drugs for formation/survival and eradication of drug-resistant CML LSCs, respectively. <i>See related commentary by Broxmeyer, p. 13</i>. <i>This article is highlighted in the In This Issue feature, p. 5</i>