miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease.
Autor: | Caserta C; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Nucera S; Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.; School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy., Barcella M; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; National Research Council, Institute for Biomedical Technologies, Segrate, Italy., Fazio G; Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Naldini MM; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Pagani R; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Pavesi F; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy., Desantis G; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Zonari E; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., D'Angiò M; Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Capasso P; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Lombardo A; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita-Salute San Raffaele University, Milan, Italy., Merelli I; National Research Council, Institute for Biomedical Technologies, Segrate, Italy., Spinelli O; Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy., Rambaldi A; Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy., Ciceri F; Vita-Salute San Raffaele University, Milan, Italy.; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy., Silvestri D; Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Valsecchi MG; Bicocca Bioinformatics, Biostatistics and Bioimaging Centre, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy., Biondi A; Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.; School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.; Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italia., Cazzaniga G; Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.; Genetics, School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy., Gentner B; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy. gentner.bernhard@hsr.it.; Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy. gentner.bernhard@hsr.it.; Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne (UNIL) and Lausanne University Hospital (CHUV), Lausanne, Switzerland. gentner.bernhard@hsr.it. |
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Jazyk: | angličtina |
Zdroj: | Leukemia [Leukemia] 2023 Oct; Vol. 37 (10), pp. 1994-2005. Date of Electronic Publication: 2023 Aug 28. |
DOI: | 10.1038/s41375-023-02009-5 |
Abstrakt: | 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). (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) |
Databáze: | MEDLINE |
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