Abstract 1314: MERTK and BCL-2 as potential therapeutic targets in early T-precursor acute lymphoblastic leukemia

Background: Early T-precursor acute lymphoblastic leukemias (ETP-ALL) account for 15% of pediatric T-cell ALL (T-ALL) cases and are characterized by an immature phenotype, resistance to therapy, and high relapse rates. MERTK receptor tyrosine kinase is ectopically expressed in ~50% of T-ALLs, particularly those with an immature T cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is specifically expressed in immature T cell precursors, is preferentially expressed in ETP-ALL compared to other T-ALLs, is essential for ETP-ALL cell survival, and is regulated downstream of MERTK in acute leukemia cells. Thus, combination therapies targeting these two proteins may be particularly effective to treat ETP-ALL. Methods: MERTK and BCL-2 mRNA expression was assessed in T-ALL patient samples using publicly available data. Loucy and PEER ETP-ALL cell lines were cultured with vehicle or MRX-2843, a dual MERTK/FLT3 inhibitor, alone or in combination with the BCL-2 inhibitor venetoclax. Phosphorylated and total MERTK were assessed by immunoblot. Cells were stained with PoPro-1-iodide and propidium iodide dyes and analyzed by flow cytometry to assess cell death. Relative cell numbers were assessed using Presto Blue reagent. Orthotopic xenografts were established in NSG or NSGS mice using luciferase-expressing Loucy cells or an ETP-ALL patient sample and leukemia burden was monitored by bioluminescence imaging or flow cytometry. MRX-2843 or saline vehicle were administered orally once daily. Median survival was determined by Kaplan-Meier analysis. Results: MERTK and BCL-2 mRNAs were expressed at significantly higher levels in ETP-ALL patient samples relative to other T-ALLs. MRX-2843 mediated a dose-dependent decrease in phosphorylated MERTK and induced dose-dependent cell death (43.2% vs 16% in vehicle-treated cultures, p