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. SIGNIFICANCE:Tumor-naïve microenvironment-induced MIR300 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 MIR300 and PP2A-activating drugs for formation/survival and eradication of drug-resistant CML LSCs, respectively.

Real-Time Molecular Monitoring in Acute Myeloid Leukemia With Circulating Tumor DNA

“…In the rapidly evolving genomic era of precision medicine, a transition towards dynamic monitoring of tumor molecular characteristics is being witnessed. In this regard, easily accessible markers that would reflect the entire heterogeneity of the tumor such as liquid biopsy including CTCs, circulating tumor-derived DNA (ctDNA), plasma cell-free DNA (cfDNA), microRNAs (miRNA), and exosomes have emerged as biomarkers with immense potential (Bronkhorst et al, 2019;Cervena et al, 2019;Silvestri et al, 2020). Plasma cfDNA facilitates non-invasive peripheral blood sampling of tumor-associated actionable alterations that are present in its ctDNA fraction and is gradually finding clinical utility in several cancers.…”

miRNome profiling of LSC-enriched CD34+CD38−CD26+ fraction in Ph+ CML-CP samples from Argentinean patients: a potential new pharmacogenomic tool

“…However, certain stem cell classes, especially pre-leukemic neoplastic stem cells may be resistant because they are slowly cycling cells and exhibit multiple forms of stem cell resistance ( Valent et al, 2012 ; Valent et al, 2013 ). TKI-resistance of CML LSC has been associated to both cell-autonomous ( Corbin et al, 2011 ; Kumari et al, 2012 ) and extrinsic factors ( Arrigoni et al, 2018 ; Zhang et al, 2018 ; Silvestri et al, 2020 ). Sometimes even LSC may survive TKI therapy and thus persist in CML patients.…”

“…One report has shown the involvement of microRNAs in TKI sensitivity in CML LSC ( Salati et al, 2017 ). Recent evidence has shown that miR-300 is a tumor suppressor microRNA able to induce quiescence in CML LSCs ( Silvestri et al, 2020 ), and that miR-126-3p regulates quiescence, self-renewal and engraftment capacity of CML LSCs ( Zhang et al, 2018 ). Advances in the characterization of aberrant expression of surface markers have allowed the prospective isolation of LSC and HSC from CML patients ( Herrmann et al, 2014 ; Warfvinge et al, 2017 ).…”

Players in Drug-Resistant Leukemia Stem/Initiating Cells and Immunity in Patients with CML in Context of Oxygen Levels: Would Collecting/Processing Cells in Hypoxia Offer Additional Information? A Next Frontier of Investigation

“…As noted by Silvestri and colleagues (1), chronic myelogenous leukemia (CML) treatment does not result in cured disease for many patients (2,3). Thus, therapeutic challenges remain.…”

“…It will be of interest to see how more stringent low oxygen assessments might affect the results reported by Silvestri and colleagues (1) and others for LS/ICs and other CS/ICs in terms of ex vivo growth characteristics, gene and protein expression patterns, and responsiveness to agents used to modulate these activities for eventual health benefit. More importantly, will this and the studies of Silvestri and colleagues (1) eventually be able to be used in a clinical setting?…”