TLX Homeodomain Oncogenes Mediate T Cell Maturation Arrest in T-ALL via Interaction with ETS1 and Suppression of TCRα Gene Expression
TLX Homeodomain Oncogenes Mediate T Cell Maturation Arrest in T-ALL via Interaction with ETS1 and Suppression of TCRα Gene Expression
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DOI：
10.1016/j.ccr.2012.02.013
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发表时间：
2012-04-17
期刊：
影响因子：
50.3
通讯作者：
Asnafi, Vahid
中科院分区：
文献类型：
--
作者：
Dadi, Saida;Le Noir, Sandrine;Asnafi, Vahid
急性淋巴细胞白血病（ALL）的特征是多步骤致癌过程导致细胞分化停滞和增殖。成熟阻滞的特异性消除构成了癌症中有希望的治疗选择，这需要对潜在的分子机制的精确理解。我们发现，在过度表达TLX 1或TLX 3的T系ALL中，皮质胸腺成熟停滞是由于TLX 1/TLX 3与ETS 1结合，导致T细胞受体（TCR）α增强体活性的抑制和TCR-J α重排的阻断。TLX 1/TLX 3消除或增强的TCR α β表达导致TCR α重排和细胞凋亡。重要的是，携带TCR α驱动的TLX 1表达的克隆的自动消退支持了TLX阳性白血病中的TLX“成瘾”，并为基于TLX 1/TLX 3破坏的靶向治疗提供了进一步的理论基础。
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.