TLX Homeodomain Oncogenes Mediate T Cell Maturation Arrest in T-ALL via Interaction with ETS1 and Suppression of TCR¦Á Gene Expression

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• 作者：Saï ; da Dadi¹ ; ³ ; ⁹ ; Sandrine Le  ; Noir¹ ; ⁹ ; Dominique Payet-Bornet³ ; ⁹ ; Ludovic Lhermitte¹ ; Joaquin Zacarias-Cabeza³ ; Julie Bergeron¹ ; Patrick Villarè ; se¹ ; Elodie Vachez³ ; Willem  ; A. Dik⁴ ; Corinne Millien¹ ; Isabelle Radford² ; Els Verhoeyen⁵ ; Franç ; ois-Loï ; c Cosset⁵ ; Arnaud Petit⁶ ; Norbert Ifrah⁷ ; Herv&#233 ; Dombret⁸ ; Olivier Hermine¹ ; Salvatore Spicuglia³ ; Anton  ; W. Langerak⁴ ; Elizabeth  ; A. Macintyre¹ ; ¹⁰ ; Bertrand Nadel³ ; ¹⁰ ; Pierre Ferrier³ ; ¹⁰ ; ^{ferrier@ciml.univ-mrs.fr} ; Vahid Asnafi¹ ; ¹⁰ ; ^{vahid.asnafi@nck.aphp.fr}
• 刊名：Cancer Cell
• 出版年：2012
• 出版时间：17 April, 2012
• 年：2012
• 卷：21
• 期：4
• 页码：563-576
• 全文大小：1805 K

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Summary

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) ¦Á enhanceosome activity and blocked TCR-J¦Á rearrangement. TLX1/TLX3 abrogation or enforced TCR¦Á¦Â expression leads to TCR¦Á rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCR¦Á-driven TLX1 expression supports TLX ¡°addiction?in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3.