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

S Dadi, S Le Noir, D Payet-Bornet, L Lhermitte, J Zacarias-Cabeza, J Bergeron, P Villarese, E Vachez, Wim Dik, C Millien, I Radford, E Verhoeyen, FL Cosset, A Petit, N Ifrah, H Dombret, O Hermine, S Spicuglia, Ton Langerak, EA MacintyreB Nadel, P Ferrier, V Asnafi

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Abstract

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) alpha enhanceosome activity and blocked TCR-J alpha rearrangement. TLX1/TLX3 abrogation or enforced TCR alpha beta expression leads to TCR alpha rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCR alpha-driven TLX1 expression supports TLX "addiction" in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3.
Original languageUndefined/Unknown
Pages (from-to)563-576
Number of pages14
JournalCancer Cell
Volume21
Issue number4
DOIs
Publication statusPublished - 2012

Research programs

  • EMC MM-02-72-02
  • EMC MM-02-72-03

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