TLX1 translocation variants and enhancer hijacking influence clinical outcome in T-cell acute lymphoblastic leukemia

The T-cell Leukemia Homeobox 1 (TLX1) oncogene is frequently deregulated in T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). In most instances, TLX1 overexpression results from its juxtaposition with a T-cell receptor (TCR) locus caused by interchromosomal translocations. However, in the subset of non-TCR-translocated TLX1-positive (non-TCR TLX1+) T-ALL cases, the underlying mechanisms driving TLX1 overexpression and their clinico-biological implications remain unclear. By integrating high-resolution data from next-generation sequencing, fluorescence in situ hybridization, karyotyping, optical genome mapping, and long-read whole-genome sequencing across a cohort of 1122 adult and pediatric T-ALL/T-LBL cases, we identified TLX1 overexpression in 11% of T-ALL/T-LBL cases, with an unexpected 14% incidence of non-TCR TLX1+ cases among TLX1+ cases. Non-TCR TLX1 + T-ALL cases show distinct clinico-biological features, including a lower frequency of cortical phenotype compared to the TCR-translocated TLX1+ (TCR TLX1+) subgroup, regardless of TLX1 expression levels. In non-TCR TLX1⁺ cases, TLX1 deregulation results mostly (83%) from the hijacking of the ANKRD1 and PCGF5 enhancer at 10q23.31 through various chromosomal aberrations. Genomic analyses revealed that these aberrations juxtapose the ANKRD1 and PCGF5 enhancer with TLX1, driving its overexpression. Importantly, survival analysis revealed that non-TCR TLX1+ patients had significantly poorer outcomes compared to their TCR TLX1⁺ counterparts (3y-OS: 55% vs. 90%, P < 0.001 and 3y-DFS: 45% vs. 75%, P = 0.02). These findings, consistent with our previous observations in TAL1-driven T-ALL, confirm that the clinico-biological impact of an oncogene is influenced by the specific mechanism underlying its deregulation.