The TLX1 oncogene drives aneuploidy in T-cell transformation

The TLX1 transcription factor oncogene plays an important role in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). However, the specific mechanisms of T-cell transformation downstream of TLX1 remain to be elucidated. Here we show that forced expression of TLX1 in transgenic mice induces T-ALL tumors with frequent deletions and mutations in Bcl11b, and identify the presence of recurrent mutations and deletions in BCL11B in 16% of human T-ALLs. Most notably, mouse TLX1 tumors were typically aneuploid and showed a marked defect in the activation of the mitotic checkpoint. Mechanistically, TLX1 directly downregulates the expression of CHEK1 and additional mitotic control genes and induces loss of the mitotic checkpoint in non transformed preleukemic thymocytes. These results identify a novel mechanism contributing to chromosomal missegregation and aneuploidy active at the earliest stages of tumor development in the pathogenesis of cancer.