MYC fails to efficiently shape malignant transformation in T-cell acute lymphoblastic leukemia. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Genes, Chromosomes & Cancer Année : 2014

MYC fails to efficiently shape malignant transformation in T-cell acute lymphoblastic leukemia.

Stéphanie Gon
Thomas Crouzet
  • Fonction : Auteur
Marie-Amélie Goujart
  • Fonction : Auteur
Gérard Michel
  • Fonction : Auteur

Résumé

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 (tgMyc(spo)) 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 tgMyc(spo) 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.

Dates et versions

hal-00940860 , version 1 (03-02-2014)

Identifiants

Citer

Marie Loosveld, Mélanie Bonnet, Stéphanie Gon, Bertrand Montpellier, Benoit Quilichini, et al.. MYC fails to efficiently shape malignant transformation in T-cell acute lymphoblastic leukemia.. Genes, Chromosomes & Cancer, 2014, 53 (1), pp.52-66. ⟨10.1002/gcc.22117⟩. ⟨hal-00940860⟩
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