Abstract A016: Novel LEF1 gene structural variants in T-cell acute lymphoblastic leukemia Patient-Derived Xenografts models

Abstract

Abstract Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by uncontrolled proliferation of immature T-cell precursors. LEF1 (Lymphoid Enhancer-Binding Factor 1) is a transcription factor that plays a crucial role in the development of T-cells. Recent studies have shown that LEF1 can affect the expression of MYC, a proto-oncogene that is frequently dysregulated in cancer. The highly expressed LEF1 gene and potentially its variants (K86E and P106L) stimulate cell growth by upregulating the expression of MYC. In T-ALL, MYC is often overexpressed, the abnormal expression of MYC propels the advancement of T-ALL and sustains the function of leukemia stem cells. The interaction between LEF1 and MYC in T-ALL is complex and involves multiple regulatory pathways, particularly the Wnt/β-catenin signaling pathway. Several studies have revealed a significant correlation between the inactivation of LEF1 and the overexpression of MYC in T-ALL. Therefore, understanding the role of LEF1 in T-ALL pathogenesis may provide new insights into the development of novel therapeutic strategies for this aggressive disease. This study shows that the novel structural variants (SVs) found in the LEF1 gene could be associated with the decreased expression of MYC. Methods: Leukemia cells derived from 6 patients with T-ALL were inoculated intravenously into immunodeficient mice tails. The burden of tumor was monitored within the peripheral blood (hCD45+), and the leukemia cells were collected once human CD45 was above 80%. Optical Genome Mapping (OGM, Bionano Genomics) and Whole Genome Sequencing (WGS) techniques were used to detect SVs and mutations. The findings were subsequently validated using polymerase chain reaction (PCR). Results: Of the 6 T-ALL models that were analyzed, two of them had SVs in the LEF1 gene. Although the expression of the LEF1 gene did not show significant changes, the expression of MYC was observed to be downregulated. The OGM analysis revealed that the second and third exons of the LEF1 gene, which are located in the β-catenin binding region, were deleted at the DNA level. The lack of complete identity between the sequences at the breakpoints could be attributed to DNA repair mechanisms. At the RNA level, the two models had distinct LEF1 mutations - E60K and P106L. Conclusion: In two of the six T-ALL models, novel SVs were found in the LEF1 gene that may decrease MYC expression compared to control samples. Further research is required to understand the relationship between LEF1 deletion and the regulation of MYC expression, as well as the role of this phenomenon in the development of T-ALL. Targeting LEF1 has emerged as a potential therapeutic strategy for the treatment of T-ALL. Citation Format: Yueying Wang, Wubin Qian, Mengting Qin, Xiaobo Chen, Jia Xue, Sheng Guo. Novel LEF1 gene structural variants in T-cell acute lymphoblastic leukemia Patient-Derived Xenografts models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A016.