Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases.

Autor:	Rodríguez-Hernández G; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Hauer J; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., Martín-Lorenzo A; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Schäfer D; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., Bartenhagen C; Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany., García-Ramírez I; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Auer F; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., González-Herrero I; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Ruiz-Roca L; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Gombert M; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., Okpanyi V; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., Fischer U; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., Chen C; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., Dugas M; Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany., Bhatia S; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., Linka RM; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany., Garcia-Suquia M; Departamento de Ciencias Biomédicas y del Diagnóstico, Área de Obstetricia y Ginecología, HUS-Universidad de Salamanca, Salamanca, Spain., Rascón-Trincado MV; Departamento de Ciencias Biomédicas y del Diagnóstico, Área de Obstetricia y Ginecología, HUS-Universidad de Salamanca, Salamanca, Spain., Garcia-Sanchez A; Departamento de Ciencias Biomédicas y del Diagnóstico, Área de Obstetricia y Ginecología, HUS-Universidad de Salamanca, Salamanca, Spain.; IBSAL, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain., Blanco O; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain., García-Cenador MB; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain., García-Criado FJ; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.; Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain., Cobaleda C; Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, 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 Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain.; Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain., Müschen M; Department of Laboratory Medicine, University of California San Francisco, San Francisco, California., Vicente-Dueñas C; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Sánchez-García I; Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Borkhardt A; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany. Arndt.Borkhardt@med.uni-duesseldorf.de.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2017 Aug 15; Vol. 77 (16), pp. 4365-4377. Date of Electronic Publication: 2017 Jun 19.
DOI:	10.1158/0008-5472.CAN-17-0701
Abstrakt:	ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase ( KDM ) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365-77. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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