Abstract: 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).
Abstract: The transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in one of the most aggressive subtypes of acute myeloid leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of CEBPA, which encodes a transcription factor required for neutrophil development and is frequently mutated in other AML subtypes. MECOM depletion is accompanied by a severe loss of CD34 and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42-kilobase CEBPA enhancer. This is partially dependent on the interaction between MECOM and its corepressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, patients with AML with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA levels. Our study directly connects 2 major players in normal and malignant hematopoiesis, MECOM and CEBPA, and unveils how MECOM maintains self-renewal by repressing CEBPA-induced differentiation.
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