Mentor Name: Kai Tan

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer affecting children and adults. Despite improvements in cytotoxic chemotherapy and stem cell transplantation, up to 20-30% of children experience relapsed/refractory disease for which the outcomes are poor. Therefore, identification of novel therapeutic approaches is a major unmet need in this disease. Navitoclax and venetoclax are BH3 mimetic drugs, which exert potent pro-apoptotic activity in several cancers. These agents are approved for clinical use in acute myeloid leukemia and mature lymphoid neoplasms, and there is significant interest in expanding their use to ALL, noting encouraging results in early phase clinical trials. In our preliminary work, we have uncovered a novel epigenetic driver of resistance to venetoclax and navitoclax in T-ALL, involving the transcriptional regulator LDB1 as its partner protein, LMO2, which is frequently overexpressed in T-ALL. Several resistance-associated genes are regulated by LDB1/LMO2 transcriptional activity and loss of LDB1 appears to restore sensitivity of T-ALL cells to navitoclax or venetoclax in vitro. Our hypothesis is that LDB1/LMO2 promotes transcriptional rewiring leading to therapy resistance and that this gene expression signature can be used to identify patients with high risk of treatment resistance. We propose to test this hypothesis by 1) characterizing the LDB1-dependent transcriptome associated with resistance in T-ALL cell lines and 2) leveraging single-cell RNA sequencing datasets from primary patient samples to identify the clonal evolution of venetoclax and/or navitoclax resistance. The findings in this proposal will expand our understanding of mechanisms of therapy resistance and provide insights into transcriptional plasticity of T-ALL with the ultimate goal of improving outcomes for patients through more personalized selection of these therapies.