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

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