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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.

T‐cell acute lymphoblastic leukemia (T‐ALL) is a rare and aggressive hematological malignancy primarily affecting adolescents and young adults and is scarce in infants and toddlers under age 3. Unlike B‐ALL, T‐ALL in this young population remains poorly characterized due to limited data and lacks evidence‐based guidelines to help clinicians determine the optimal treatment approach. In this study, we conducted a comprehensive genetic analysis of infant/toddler T‐ALL cases from a French national cohort, utilizing high‐throughput targeted sequencing, optical genome mapping, and RNA sequencing. Genetic analysis revealed the absence of TLX1/3 dysregulation. Instead, we identified a significant prevalence of NKX2 rearrangements (n = 9, 33%), co‐occurring with MYB alterations (n = 5/9) or chromothripsis‐like events (n = 3/9). Additional findings included TAL1/‐like anomalies (30%), STAG2::LMO2 (15%), ETS rearrangements (15%), and rarely, KMT2A rearrangements (7%). Comparative analyses with 245 patients aged 3–18 years, enrolled in the pediatric FRALLE2000T French protocol, underscored the distinct clinical and genetic profiles of infants/toddlers. Despite presenting with higher rates of hyperleukocytosis and slower responses to treatment, they demonstrated comparable survival outcomes to older pediatric patients, with a 5‐year overall survival (OS) rate of 75.4% (95% confidence interval [CI]: 60.0%–94.8%) versus 75.2% (95% CI: 69.8%–81.1%), p = 0.86. Notably, alterations in NKX2, KMT2A, and STAG2::LMO2 delineated oncogenic subgroups exhibiting a remarkable 100% OS rate, while patients with TAL1 or ETS dysregulation experienced less favorable outcomes. This was further supported by analyses of data from the COG AALL0434 trial, enhancing our understanding of T‐ALL in infants/toddlers. Large‐scale collaborative studies remain essential to confirm these findings and refine treatment strategies.

The reintegration of excised signal joints resulting from human V(D)J recombination was described as a potent source of genomic instability in human lymphoid cancers. However, such molecular events have not been recurrently reported in clinical patient lymphoma/leukemia samples. Using a specifically designed NGS-capture pipeline, we here demonstrated the reintegration of T-cell receptor excision circles (TRECs) in 20/1533 (1.3%) patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Remarkably, the reintegration of TREC recurrently targeted the tumor suppressor gene, ZFP36L2, in 17/20 samples. Thus, our data identified a new and hardly detectable mechanism of gene deregulation in lymphoid cancers providing new insights in human oncogenesis.