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Caserta, Carolina; Nucera, Silvia; Barcella, Matteo; Fazio, Grazia; Naldini, Matteo Maria; Pagani, Riccardo; Pavesi, Francesca; Desantis, Giacomo; Zonari, Erika; D'Angiò, Mariella; Capasso, Paola; Lombardo, Angelo; Merelli, Ivan; Spinelli, Orietta; Rambaldi, Alessandro; Ciceri, Fabio; Silvestri, Daniela; Valsecchi, Maria Grazia; Biondi, Andrea; Cazzaniga, Giovanni; Gentner, Bernhard
Leukemia, 10/2023, Volume: 37, Issue: 10Journal Article
Complete elimination of B-cell acute lymphoblastic leukemia (B-ALL) by a risk-adapted primary treatment approach remains a clinical key objective, which fails in up to a third of patients. Recent evidence has implicated subpopulations of B-ALL cells with stem-like features in disease persistence. We hypothesized that microRNA-126, a core regulator of hematopoietic and leukemic stem cells, may resolve intratumor heterogeneity in B-ALL and uncover therapy-resistant subpopulations. We exploited patient-derived xenograft (PDX) models with B-ALL cells transduced with a miR-126 reporter allowing the prospective isolation of miR-126(high) cells for their functional and transcriptional characterization. Discrete miR-126(high) populations, often characterized by MIR126 locus demethylation, were identified in 8/9 PDX models and showed increased repopulation potential, in vivo chemotherapy resistance and hallmarks of quiescence, inflammation and stress-response pathway activation. Cells with a miR-126(high) transcriptional profile were identified as distinct disease subpopulations by single-cell RNA sequencing in diagnosis samples from adult and pediatric B-ALL. Expression of miR-126 and locus methylation were tested in several pediatric and adult B-ALL cohorts, which received standardized treatment. High microRNA-126 levels and locus demethylation at diagnosis associate with suboptimal response to induction chemotherapy (MRD > 0.05% at day +33 or MRD+ at day +78).
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