1020 – TRIMODAL SINGLE-CELL PROFILING REVEALS EPIGENETIC INTRATUMOR HETEROGENEITY IN T CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL)

Intratumor heterogeneity (ITH) is a main cause of therapy resistance and relapse in leukemia. While genetic mutations play an important role in clonal evolution during disease development, accumulating evidence suggests that non-genetic mechanisms are also major drivers of ITH. Here we used single-cell trimodal approaches measuring simultaneously RNA, chromatin and over 150 cell surface proteins as well as gene regulatory network construction to decipher the epigenetic basis of tumor heterogeneity in T cell acute lymphoblastic leukemia (T-ALL), an aggressive cancer of thymocytes with a high relapse rate. Our results reveal an unexpected contribution of non-genetic mechanisms in the tumor-initiating process in T-ALL, and allowed us to identify patient-specific combinations of cell surface proteins with critical implications for future targeted therapies.