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dc.contributor.authorAbollo-Jiménez, Fernando-
dc.contributor.authorCampos-Sánchez, Elena-
dc.contributor.authorToboso-Navasa, Amparo-
dc.contributor.authorVicente-Dueñas, Carolina-
dc.contributor.authorGonzález-Herrero, Inés-
dc.contributor.authorAlonso-Escudero, Esther-
dc.contributor.authorGonzález, Marcos-
dc.contributor.authorSegura, Víctor-
dc.contributor.authorBlanco, Óscar-
dc.contributor.authorMartínez-Climent, José Ángel-
dc.contributor.authorSánchez García, Isidro-
dc.contributor.authorCobaleda, César-
dc.identifierdoi: 10.4161/cc.28629-
dc.identifiere-issn: 1551-4005-
dc.identifierissn: 1538-4101-
dc.identifier.citationCell Cycle 13(11): 1717-1726 (2014)-
dc.description.abstractIn 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.-
dc.description.sponsorshipResearch at C.C.’s lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias, CSIC P.I.E., Junta de Castilla y León, and from an institutional grant from the Fundación Ramón Areces. Research in ISG group is partially supported by FEDER and by MICINN (SAF2012-32810), by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by NIH grant (R01 CA109335-04A1), the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program), by Junta de Castilla y León (BIO/SA06/13) and by “Proyecto en red de investigación en células madre tumorales” supported by Obra Social Kutxa y Consejería de Sanidad de la Junta de Castilla y Leon. C.V.D.’s research is supported by Junta de Castilla y León (proyecto de investigación en biomedicina SAN/39/2010). J.A.M.C.’s research is supported by the Instituto de Salud Carlos III (ISCIII), grants FIS-PI12/00202 and RTICC-RD12/0036/0063. All Spanish funding is co-sponsored by the European Union FEDER program. I.S.G. is an API lab of the EuroSyStem project and a partner of DECIDE European network. F.A.-J. and E.C.S. were supported by Spanish Ministry of Science and Innovation fellowships. E.C.-S. was a “Residencia de Estudiantes” Fellow. A.T.N. was the recipient of a “Beca de Postgrado de la Fundación Ramón Areces/UAM.”-
dc.publisherLandes Bioscience-
dc.publisherTaylor & Francis-
dc.subjectT-cell development-
dc.subjectDNA methylation-
dc.subjectChronic myelogenous leukemia-
dc.subjectBlast crisis-
dc.titleLineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis-
dc.description.versionPeer Reviewed-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderConsejo Superior de Investigaciones Científicas (España)-
dc.contributor.funderJunta de Castilla y León-
dc.contributor.funderFundación Ramón Areces-
dc.contributor.funderEuropean Commission-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderNational Institutes of Health (US)-
dc.contributor.funderObra Social Kutxa-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderCSIC - Residencia de Estudiantes-
dc.contributor.funderUniversidad Autónoma de Madrid-
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