LEF1 intragenic deletion induces a dominant-negative isoform and unveils a Wnt/β-catenin vulnerability in T-ALL.

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 (LEF)/T-cell factor family of DNA-binding transcription factors, known for their interaction with nuclear β-catenin in the context of the Wnt signaling pathway. Although the implication of LEF1 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 patients with T-ALL enrolled in the FRALLE-2000 (French group for childhood ALL) and GRAALL 2003-2005 (Group for Research on Adult Acute Lymphoblastic Leukemia) trials, 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 T-cell receptor signaling, which can be exploited as a therapeutic strategy to enhance chemosensitivity in LEF1-deleted T-ALL cases. The trials were registered at www.clinicaltrials.gov as #NCT00222027 (GRAALL 2003) and #NCT00327678 (GRAALL 2005); FRALLE2000T protocol (FRALLE-2000).