Abstract
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.
Competing Interest Statement
MK discloses grants and other from AbbVie, grants and other from F. Hoffman La-Roche, grants and other from Stemline Therapeutics, grants and other from Forty-Seven, grants from Eli Lilly, grants from Cellectis, grants from Calithera, grants from Ablynx, grants from Agios, grants from Ascentage, grants from Astra Zeneca, other from Reata Pharmaceutical, grants from Rafael Pharmaceutical, grants from Sanofi, other from Janssen, grants and other from Genentech. AL discloses that he has consulted for and received research support from AbbVie, Novartis, and Astra-Zeneca. AL is an equity-holding member of the scientific advisory boards of Zentalis Pharmaceuticals, Flash Therapeutics, and Dialectic Therapeutics. JSG has received research funding from AbbVie, Genentech, Prelude, AstraZeneca, and Pfizer. She has served on the AbbVie, Astellas and Takeda advisory boards. All other authors have no conflicts of interest to disclose.