Author/Authors :
Dadi، نويسنده , , Saïda and Le Noir، نويسنده , , Sandrine and Payet-Bornet، نويسنده , , Dominique and Lhermitte، نويسنده , , Ludovic and Zacarias-Cabeza، نويسنده , , Joaquin and Bergeron، نويسنده , , Julie and Villarèse، نويسنده , , Patrick and Vachez، نويسنده , , Elodie and Dik، نويسنده , , Willem A. and Millien، نويسنده , , Corinne and Radford، نويسنده , , Isabelle and Verhoeyen، نويسنده , , Els and Cosset، نويسنده , , François-Loïc and Petit، نويسنده , , Arnaud and Ifrah، نويسنده , , Norbert and Dombret، نويسنده , , Hervé and Hermine، نويسنده , , Olivier and Spicuglia، نويسنده , , Salvatore and Langerak، نويسنده , , Anton W. and Macintyre، نويسنده , , Elizabeth A. and Nadel، نويسنده , , Bertrand and Ferrier، نويسنده , , Pierre and Asnafi، نويسنده , , Vahid، نويسنده ,
Abstract :
Summary
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.
