Publication: TLX homeodomain oncogenes mediate T cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCRα gene expression.

Publié dans: Cancer Cell 2012 Apr; 21(4): 563-76

Auteurs: Dadi S, Le Noir S, Payet-Bornet D, Lhermitte L, Zacarias-Cabeza J, Bergeron J, Villarèse P, Vachez E, Dik WA, Millien C, Radford I, Verhoeyen E, Cosset FL, Petit A, Ifrah N, Dombret H, Hermine O, Spicuglia S, Langerak AW, Macintyre EA, Nadel B, Ferrier P, Asnafi V

Résumé

Acute lymphoblastic leukemias (ALLs) are characterized by multistep oncogenic processes leading to cell-differentiation arrest and proliferation. Specific abrogation of maturation blockage constitutes a promising therapeutic option in cancer, which requires precise understanding of the underlying molecular mechanisms. We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. TLX1/TLX3 abrogation or enforced TCRαβ expression leads to TCRα rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCRα-driven TLX1 expression supports TLX “addiction” in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3.

Lien vers Pubmed [PMID] – 22516263

Lien vers le DOI – 10.1016/j.ccr.2012.02.013