Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on MIR300 Antiproliferative and PP2A-Activating Functions.
Giovannino SilvestriRossana TrottaLorenzo StramucciJustin J EllisJason G HarbPaolo NevianiShuzhen WangAnn-Kathrin EisfeldChristopher J WalkerBin ZhangKlara SrutovaCarlo Gambacorti-PasseriniGabriel PinedaCatriona H M JamiesonFabio StagnoPaolo VigneriGeorgios NteliopoulosPhilippa C MayAlistair G ReidRamiro GarzonDenis-Claude RoyMoutuaata M MoutuouMartin GuimondPeter HoklandMichael W DeiningerGarrett FitzgeraldChristopher HarmanFrancesco DazziDragana MilojkovicJane F ApperleyGuido MarcucciJianfei QiKaterina Machova PolakovaYing ZouXiaoxuan FanMaria R BaerBruno CalabrettaDanilo PerrottiPublished in: Blood cancer discovery (2022)
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.
Keyphrases
- nk cells
- long noncoding rna
- drug resistant
- cell proliferation
- long non coding rna
- stem cells
- immune response
- chronic myeloid leukemia
- bone marrow
- multidrug resistant
- cell cycle
- acinetobacter baumannii
- acute myeloid leukemia
- signaling pathway
- oxidative stress
- end stage renal disease
- acute lymphoblastic leukemia
- endoplasmic reticulum stress
- tyrosine kinase
- cell death
- small molecule
- newly diagnosed
- peritoneal dialysis
- gene expression
- pseudomonas aeruginosa
- toll like receptor
- dna methylation
- neural stem cells
- pi k akt
- combination therapy
- stress induced
- adverse drug
- electronic health record
- endothelial cells