TLX Homeodomain Oncogenes Mediate T Cell Maturation Arrest in T-ALL via Interaction with ETS1 and Suppression of TCR alpha Gene Expression
Menée à partir d'échantillons de sang et de moelle osseuse prélevés sur des patients atteints d'une leucémie lymphoblastique aiguë, cette étude met en évidence un mécanisme d'interaction entre les facteurs de transcription TLX1 ou TLX3 et la protéine proto-oncogénique ETS1
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) ± enhanceosome activity and blocked TCR-J± rearrangement. TLX1/TLX3 abrogation or enforced TCR±² expression leads to TCR± rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCR±-driven TLX1 expression supports TLX addiction in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3. º TLX1 and TLX3 proteins interact with the ETS1 proto-oncogene in T-ALL º TLX-ETS1 protein interaction blocks TCR± rearrangement via Enhancer-alpha repression º TLX inactivation and TCR±² expression induce redifferentiation and apoptosis º Sustained TLX expression is required for leukemic transformation.
Cancer cell , résumé, 2011