Cancer induction by restriction of oncogene expression to the stem cell compartment

This is an open-access article distributed under the terms of the Creative Commons Attribution License.In human cancers, all cancerous cells carry the oncogenic genetic lesions. However, to elucidate whether cancer is a stem cell-driven tissue, we have developed a strategy to limit oncogene expression to the stem cell compartment in a transgenic mouse setting. Here, we focus on the effects of the BCR-ABLp210 oncogene, associated with chronic myeloid leukaemia (CML) in humans. We show that CML phenotype and biology can be established in mice by restricting BCR-ABLp210 expression to stem cell antigen 1 (Sca1)+ cells. The course of the disease in Sca1-BCR-ABLp210 mice was not modified on STI571 treatment. However, BCR-ABLp210-induced CML is reversible through the unique elimination of the cancer stem cells (CSCs). Overall, our data show that oncogene expression in Sca1+ cells is all that is required to fully reprogramme it, giving rise to a full-blown, oncogene-specified tumour with all its mature cellular diversity, and that elimination of the CSCs is enough to eradicate the whole tumour. © 2009 European Molecular Biology Organization | Some Rights Reserved.Research in our group is supported partially by FEDER and by MEC (SAF2006-03726), Junta de Castilla y León (CSI13A08 and GR15), FIS (PI050087), Federación de Cajas de Ahorro Castilla y León (I Convocatoria de Ayudas para Proyectos de Investigación Biosanitaria con Células Madre), CDTEAM project (CENIT-Ingenio 2010) and MEC OncoBIO Consolider-Ingenio 2010 (ref. CSD2007-0017). CC is a Spanish ‘Ramón y Cajal’ investigator from the Spanish Ministerio de Educación y Ciencia. Research at CC’s lab is partially supported by Fondo de Investigaciones Sanitarias (PI04/0261; PI080164), Junta de Castilla y León (SA087A06) and Fundación de Investigación Médica MM. MS-M is a Spanish ‘Ramón y Cajal’ investigator from the Spanish Ministerio de Educación y Ciencia. Research at MS-M’s lab is supported by FIS (grant no. PI041271) and Junta de Castilla y León (SA085A06). Research by AO is supported by a grant from the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain (IISCIII-RTICC RD06/0020/0035-FEDER).Peer Reviewe