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bioRxiv · 10.1101/2021.08.19.456932

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

Olesinski, E. A.·Bhatia, K. S.·Garica, J. S.·Jain, N.·Letai, A.·Konopleva, M.·Bhatt, S.
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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 SignificanceAdults 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.

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Olesinski, E. A., Bhatia, K. S., Garica, J. S., Jain, N., Letai, A., Konopleva, M., Bhatt, S.. 2021-08-19. BH3 Profiling Identifies Selective BCL-2 Dependence of Adult Early T-cell Progenitor (ETP) Subtype of Acute Lymphoblastic Leukemia (ALL) Patients. https://doi.org/10.1101/2021.08.19.456932

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