Immune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice.
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- Academic Journal
- Authors
- Isidro-Hernández M; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Casado-García A; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Oak N; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Alemán-Arteaga S; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Ruiz-Corzo B; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Martínez-Cano J; Immune system development and function Unit, Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas -Universidad Autónoma de Madrid), Madrid, Spain.; Mayado A; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Servicio de Citometría, Departamento de Medicina, Biomedical Research Networking Centre on Cancer CIBER-CIBERONC (CB16/12/00400), Institute of Health Carlos III, and Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain.; Sánchez EG; Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.; Blanco O; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.; Gaspar ML; Immunobiology Department, Carlos III Health Institute, 28220, Majadahonda (Madrid), Spain.; Orfao A; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Servicio de Citometría, Departamento de Medicina, Biomedical Research Networking Centre on Cancer CIBER-CIBERONC (CB16/12/00400), Institute of Health Carlos III, and Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain.; Alonso-López D; Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain.; De Las Rivas J; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain.; Riesco S; Department of Pediatrics, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, Salamanca, 37007, Spain.; Prieto-Matos P; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Department of Pediatrics, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, Salamanca, 37007, Spain.; González-Murillo Á; Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.; Criado FJG; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Departamento de Cirugía, , Universidad de Salamanca, Salamanca, Spain.; Cenador MBG; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Departamento de Cirugía, , Universidad de Salamanca, Salamanca, Spain.; Ramírez-Orellana M; Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.; de Andrés B; Immunobiology Department, Carlos III Health Institute, 28220, Majadahonda (Madrid), Spain.; Vicente-Dueñas C; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. cvd@usal.es.; Department of Pediatrics, Hospital Universitario de Salamanca, Paseo de San Vicente, 58-182, Salamanca, 37007, Spain. cvd@usal.es.; Cobaleda C; Immune system development and function Unit, Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas -Universidad Autónoma de Madrid), Madrid, Spain. cesar.cobaleda@csic.es.; Nichols KE; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. Kim.Nichols@STJUDE.ORG.; Sánchez-García I; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Campus M. de Unamuno s/n, Salamanca, Spain. isg@usal.es.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. isg@usal.es.
- Source
- Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
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- Language
- English
The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5 +/- B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5 +/- Myd88 +/- mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5 +/- mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.
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