Extracellular vesicle microRNAs contribute to Notch signaling pathway in T-cell acute lymphoblastic leukemia

Molecular Cancer

Correspondence

Giovanni Rossi¹  Orazio Palumbo²  Roberto Cuttano³  Fabrizio Bianchi³  Tommaso Colangelo³  Valentina Melocchi³  Francesco Mazzarelli³  Elisabetta De Santis⁴  Patrizio Panelli⁴  Vincenzo Giambra⁴  Francesco Tamiro⁴ 

[1] Department of Hematology and Stem Cell Transplant Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, FG, Italy;Division of Medical Genetics, Fondazione IRCCS Casa Sollievo Della Sofferenza, 71013, San Giovanni Rotondo, FG, Italy;Unit of Cancer Biomarker, Fondazione IRCCS Casa Sollievo Della Sofferenza, Viale Padre Pio 7, 71013, San Giovanni Rotondo, FG, Italy;Unit of Hematopathology, Fondazione IRCCS Casa Sollievo Della Sofferenza, Viale Padre Pio 7, 71013, San Giovanni Rotondo, FG, Italy;

关键词: T-cell acute lymphoblastic leukemia;    microRNAs;    Exosomes;    Extracellular vesicles;    Gene expression;   

DOI  :  10.1186/s12943-022-01698-3

 received in 2022-02-26, accepted in 2022-12-07,  发布年份 2022

来源: Springer

【 摘 要 】

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive T-cell malignancy characterized by genotypically-defined and phenotypically divergent cell populations, governed by adaptive landscapes. Clonal expansions are associated to genetic and epigenetic events, and modulation of external stimuli that affect the hierarchical structure of subclones and support the dynamics of leukemic subsets. Recently, small extracellular vesicles (sEV) such as exosomes were also shown to play a role in leukemia. Here, by coupling miRNome, bulk and single cell transcriptome profiling, we found that T-ALL-secreted sEV contain NOTCH1-dependent microRNAs (EV-miRs), which control oncogenic pathways acting as autocrine stimuli and ultimately promoting the expansion/survival of highly proliferative cell subsets of human T-cell leukemias. Of interest, we found that NOTCH1-dependent EV-miRs mostly comprised members of miR-17-92a cluster and paralogues, which rescued in vitro the proliferation of T-ALL cells blocked by γ-secretase inhibitors (GSI) an regulated a network of genes characterizing patients with relapsed/refractory early T-cell progenitor (ETP) ALLs. All these findings suggest that NOTCH1 dependent EV-miRs may sustain the growth/survival of immunophenotypically defined cell populations, altering the cell heterogeneity and the dynamics of T-cell leukemias in response to conventional therapies.

【 授权许可】

CC BY   
© The Author(s) 2022

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