LEF1 Intragenic Deletion Induces a Dominant-Negative isoform and unveils a Wnt/β3-Catenin Vulnerability in T-ALL Available to Purchase

• LEF1 intragenic deletion is the most frequent LEF1 alteration in T-ALL and leads to a dominant-negative isoform.

• LEF1 intragenic deletion confers a therapeutic targetable dependence on the Wnt/ᵬ3-catenin pathway.

T-cell acute lymphoblastic leukemia (T-ALL) represents a group of aggressive hematological malignancies characterized by unfavorable prognosis, urging the need for innovative therapeutic strategies. LEF1 is a member of the lymphoid enhancer factor/T-cell factor (LEF/TCF) family of DNA-binding transcription factors, known for their interaction with nuclear β-catenin in the context of the Wnt signaling pathway. Although LEF1's implication in colon cancer is well-documented, its clinical relevance and functional consequences remain elusive in T-ALL. In this study, we provide valuable insights into the prevalence and significance of LEF1 alterations in a comprehensive cohort of 474 pediatric and adult T-ALL patients enrolled in the FRALLE 2000 and GRAALL-2003-2005 trials (NCT00222027; NCT00327678) respectively. LEF1 alterations were detected in 63 cases (13%), including 9 point-mutations (14.3%), 18 large deletions (28.6%), and - strikingly - 36 focal deletions (57.1%), which emerge as the most recurrent subtype. LEF1-altered cases were associated with increased central nervous system involvement and improved initial treatment response. Importantly, we unveil the existence of a previously undescribed dominant-negative LEF1 isoform resulting from focal deletions of the exons 2-3. This novel truncated protein, previously unreported in the literature, is associated with the disruption of the Wnt pathway and TCR signaling, which can be exploited as a therapeutic strategy to enhance chemosensitivity in LEF1-deleted T-ALL cases.