BH3 Profiling Identifies Selective BCL-2 Dependence of Adult Early T-cell Progenitor (ETP) Subtype of Acute Lymphoblastic Leukemia (ALL) Patients

Early T-cell precursor (ETP) acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of T-ALL and is associated with poor survival outcomes with chemotherapy. We previously showed that maturation stage of thymocytes distinguishes pro-survival dependencies of pediatric ETP-ALL (BCL-2 dependent) from non-ETP-ALL (BCL-XL dependent). Comparable data in adults are lacking. Our present study focuses on characterizing functional dependencies of adult ETP-ALL and T-ALL on BCL-2 family proteins. Using BH3 profiling on primary tumors, we report that similar to pediatric ALL, adult ETP-ALL is primarily dependent on BCL-2; however, unlike pediatric ALL, adult non-ETP-ALL is co-dependent on both BCL-2 and BCL-XL for survival. By measuring direct mitochondrial permeabilization and cell viability assays, we validated that BH3 profiling predicted on-target cytotoxicity of venetoclax in adult ETP-ALL and navitoclax plus venetoclax in adult T-ALL. These findings provide pre-clinical evidence for venetoclax and navitoclax as potentially efficacious combination therapy for adults with T-ALL. Statement of Significance Adults with relapsed T-ALL have poor prognosis and represent an unmet need for novel treatments. We report that adult ETP-ALL is dependent on BCL-2 for survival, similar to pediatric ETP-ALL. However, adult non-ETP-ALL is heterogeneously dependent on both BCL-2 and BCL-XL. We characterize key dependencies on BCL-2 family proteins to direct BH3 mimetics therapy in T-ALL patients.