miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease

• Published in: Leukemia 2023-10, Vol.37 (10), p.1994-2005
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 42/44; 631/67; 631/67/1990/283/2125; 64/60; 96; 96/35; Acute lymphoblastic leukemia; Adult; Burkitt Lymphoma; Cancer Research; Cell activation; Cell culture; Chemoresistance; Chemotherapy; Child; Critical Care Medicine; Demethylation; Diagnosis; Gene sequencing; Health services; Hematology; Heterogeneity; Humans; Intensive; Internal Medicine; Leukemia; Lymphatic leukemia; Lymphocytes B; Medicine; Medicine & Public Health; Methylation; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Minimal residual disease; miRNA; Neoplasm, Residual - genetics; Oncology; Patients; Pediatrics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Repopulation; Ribonucleic acid; RNA; Stem cells; Subpopulations; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-023-02009-5

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).