Marie Loosveld and Mélanie Bonnet contributed equally to this work.
MYC fails to efficiently shape malignant transformation in T-cell acute lymphoblastic leukemia
Version of Record online: 12 OCT 2013
Copyright © 2013 Wiley Periodicals, Inc.
Genes, Chromosomes and Cancer
Volume 53, Issue 1, pages 52–66, January 2014
How to Cite
Loosveld, M., Bonnet, M., Gon, S., Montpellier, B., Quilichini, B., Navarro, J.-M., Crouzet, T., Goujart, M.-A., Chasson, L., Morgado, E., Picard, C., Hernandez, L., Fossat, C., Gabert, J., Michel, G., Nadel, B. and Payet-Bornet, D. (2014), MYC fails to efficiently shape malignant transformation in T-cell acute lymphoblastic leukemia. Genes Chromosom. Cancer, 53: 52–66. doi: 10.1002/gcc.22117
Supported by: Grants from la Fondation pour la Recherche Médicale, Grant number: #INE2003114116, from Le Conseil Général des Bouches du Rhône, from INCa (PLBIO09 ‘MYC ALL'), from la Fondation de France, Grant number: #2008001490, institutional grants from INSERM and CNRS, Canceropôle PACA, Ligue Nationale Contre le Cancer (LNCC), and the French Society of Hematology (SFH); MB was a recipient of fellowships from the LNCC and the Ministère de l'Enseignement Supérieur et de la Recherche. ML is a recipient of a fellowship from INCa, Grant number: #ASC12035ASA. BN is a recipient of a Contrat d'Interface INSERM/Assistance Publique-Hôpitaux de Marseille (HP-HM). SG was supported by Grant number: CDA0034/2007 from the Human Frontier Science Organization.
- Issue online: 18 NOV 2013
- Version of Record online: 12 OCT 2013
- Manuscript Accepted: 17 SEP 2013
- Manuscript Received: 26 FEB 2013
MYC is a potent oncogene involved in ∼70% of human cancers, inducing tumorigenesis with high penetrance and short latency in experimental transgenic models. Accordingly, MYC is recognized as a major driver of T-cell acute lymphoblastic leukemia (T-ALL) in human and zebrafish/mouse models, and uncovering the context by which MYC-mediated malignant transformation initiates and develops remains a considerable challenge. Because MYC is a very complex oncogene, highly dependent on the microenvironment and cell-intrinsic context, we generated transgenic mice (tgMycspo) in which ectopic Myc activation occurs sporadically (<10−6 thymocytes) within otherwise normal thymic environment, thereby mimicking the unicellular context in which oncogenic alterations initiate human tumors. We show that while Myc+ clones in tgMycspo mice develop and initially proliferate in thymus and the periphery, no tumor or clonal expansion progress in aging mice (n = 130), suggesting an unexpectedly low ability of Myc to initiate efficient tumorigenesis. Furthermore, to determine the relevance of this observation in human pathogenesis we analyzed a human T-ALL case at diagnosis and relapse using the molecular stigmata of V(D)J recombination as markers of malignant progression; we similarly demonstrate that despite the occurrence of TAL1 and MYC translocations in early thymocyte ontogeny, subsequent oncogenic alterations were required to drive oncogenesis. Altogether, our data suggest that although central to T-ALL, MYC overexpression per se is inefficient in triggering the cascade of events leading to malignant transformation. © 2013 Wiley Periodicals, Inc.