Department of Hematologye, Université de Médecine Paris Descartes Sorbonne Cité, Centre National de la Recherche Scientifique (CNRS), France.
Cancer Cell. 2012 Apr 17;21(4):563-76. doi: 10.1016/j.ccr.2012.02.013.
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) 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.
急性淋巴细胞白血病（ALL）的特征是多步致癌过程，导致细胞分化阻滞和增殖。特异性消除成熟阻断是癌症的一种有前途的治疗选择，这需要对潜在的分子机制有精确的理解。我们表明，过度表达 TLX1 或 TLX3 的 T 细胞系 ALL 中的皮质胸腺成熟阻滞是由于 TLX1/TLX3 与 ETS1 结合，导致 T 细胞受体 (TCR)α增强子活性受到抑制，并且 TCR-Jα 重排受阻。TLX1/TLX3 的消除或强制 TCRαβ 表达导致 TCRα 重排和凋亡。重要的是，携带 TCRα 驱动的 TLX1 表达的克隆的自动消失支持 TLX 在 TLX 阳性白血病中的“成瘾”，并为基于破坏 TLX1/TLX3 的靶向治疗提供了进一步的理由。
