title: MYC fails to efficiently shape malignant transformation in T-cell acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, 13288, Marseille, France; INSERM U1104; CNRS UMR7280, 13288, Marseille, France; Department of Hematology, AP-HM La Timone, 13385, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Loosveld
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bonnet
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gon
authors.forename: Bertrand
authors.initials: B
authors.lastname: Montpellier
authors.forename: Benoit
authors.initials: B
authors.lastname: Quilichini
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Navarro
authors.forename: Thomas
authors.initials: T
authors.lastname: Crouzet
authors.forename: Marie-Amélie
authors.initials: MA
authors.lastname: Goujart
authors.forename: Lionel
authors.initials: L
authors.lastname: Chasson
authors.forename: Ester
authors.initials: E
authors.lastname: Morgado
authors.forename: Christophe
authors.initials: C
authors.lastname: Picard
authors.forename: Lucie
authors.initials: L
authors.lastname: Hernandez
authors.forename: Chantal
authors.initials: C
authors.lastname: Fossat
authors.forename: Jean
authors.initials: J
authors.lastname: Gabert
authors.forename: Gérard
authors.initials: G
authors.lastname: Michel
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nadel
authors.forename: Dominique
authors.initials: D
authors.lastname: Payet-Bornet
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D016259:Genes, myc / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012008:Recurrence; D014178:Translocation, Genetic; D060152:V(D)J Recombination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C071236:STIL protein, human