title: Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis.
abstract: In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis.
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer; CSIC/ Universidad de Salamanca; Campus M. de Unamuno; Institute of Biomedical Research of Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Abollo-Jiménez
authors.affiliation: Centro de Biología Molecular Severo Ochoa; CSIC/Universidad Autónoma de Madrid; Campus de Cantoblanco; Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Campos-Sánchez
authors.affiliation: Centro de Biología Molecular Severo Ochoa; CSIC/Universidad Autónoma de Madrid; Campus de Cantoblanco; Madrid, Spain; Current affiliation: Immunity and Cancer Laboratory; London Research Institute; Cancer Research UK; London, UK.
authors.forename: Amparo
authors.initials: A
authors.lastname: Toboso-Navasa
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer; CSIC/ Universidad de Salamanca; Campus M. de Unamuno; Institute of Biomedical Research of Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Vicente-Dueñas
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer; CSIC/ Universidad de Salamanca; Campus M. de Unamuno; Institute of Biomedical Research of Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: González-Herrero
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer; CSIC/ Universidad de Salamanca; Campus M. de Unamuno; Institute of Biomedical Research of Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Alonso-Escudero
authors.affiliation: Department of Hematology, University Hospital of Salamanca; Institute of Biomedical Research of Salamanca; Salamanca, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: González
authors.affiliation: Bioinformatics Unit; Center for Applied Medical Research; University of Navarra; Pamplona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Segura
authors.affiliation: Departamento de Anatomía Patológica; Universidad de Salamanca; Salamanca, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Blanco
authors.affiliation: Division of Oncology; Center for Applied Medical Research (CIMA); University of Navarra; Pamplona, Spain.
authors.forename: José Angel
authors.initials: JA
authors.lastname: Martínez-Climent
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer; CSIC/ Universidad de Salamanca; Campus M. de Unamuno; Institute of Biomedical Research of Salamanca (IBSAL); Salamanca, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Sánchez-García
authors.affiliation: Centro de Biología Molecular Severo Ochoa; CSIC/Universidad Autónoma de Madrid; Campus de Cantoblanco; Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Cobaleda
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018450:Disease Progression; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D000099266:Engrailed 2 Protein
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000099266:Engrailed 2 Protein
keywords: DNA methylation; T-cell development; blast crisis; chronic myelogenous leukemia; engrailed-2