TLX3 (T cell leukemia homeobox 3) is a homeobox transcription factor that plays a critical oncogenic role in T-cell acute lymphoblastic leukemia (T-ALL). TLX3 functions as a sequence-specific DNA-binding transcription factor that regulates gene expression in the nucleus and chr5 1. In normal development, TLX3 is involved in T-cell differentiation, but its ectopic expression in approximately 12-20% of T-ALL cases causes differentiation arrest at the cortical/postcortical stage of T-cell development 23. Mechanistically, TLX3 exerts its oncogenic effects through multiple pathways: it directly activates miR-125b expression by binding and transactivating LINC00478, which promotes T-cell transformation and blocks normal differentiation partly through repression of Ets1 and CBFβ 4. TLX3 also directly represses TLE4, a transcriptional repressor, which enhances its oncogenic function 5. TLX3-positive T-ALL frequently cooperates with FLT3-ITD mutations, particularly in pediatric cases, and this combination confers IL-7 independent growth 53. Despite its clear biological significance, TLX3 expression does not appear to be a significant prognostic indicator in pediatric T-ALL 6. TLX3 can also be activated through chr5 rearrangements like TLX3::BCL11B in rare mixed phenotype acute leukemias 7.