Abstract P30: Therapeutic activation of pre-B-cell receptor signaling in high-risk pediatric ALL: exploiting TCF3 and MYC-linked vulnerabilities

Abstract High-risk pediatric Acute Lymphoblastic Leukemia (ALL) is insufficiently addressed by current treatment options, and generally patients may benefit from safety and efficacy improvements if eligible for targeted therapies. Using a comprehensive panel of 84 pediatric ALL cell lines representing diverse molecular phenotypes, we developed a platform combining multi-omics profiling and drug response screening to link these molecular phenotypes with mechanisms of treatment response. Our results revealed that PKC activation leads to significant toxicity for specific cell line models, with an especially notable efficacy in cells harboring MEF2D rearrangements and TCF3-HLF fusions. We conducted a comprehensive analysis using quantitative, functional and chemical proteome profiling to investigate the impact of pre-B-cell receptor (BCR) signaling activation, identifying a link between activated pre-BCR signaling toxicity and a TCF3 and MYC driven differentiation program. This vulnerability aligns with observed parallels in apoptosis mechanisms during B- and T- lymphocyte development, suggesting a therapeutic angle that exploits a developmental checkpoint. Further, we observed that resistant cell lines have similar induction of toxicity effector responses during PKC activation, but are protected by induction of TCF3 bHLH domain functions and histone acetylation changes. A synergy screen was conducted between PKC activator bryostatin-1 and 528 clinically approved or investigational oncology compounds, using normal bone marrow responses as a healthy reference. This revealed that non-responsive leukemia cell lines can be sensitized to PKC activation effects when combining PKC activation with epigenetic modifiers, indicating an enhanced therapeutic potential. The activation of pre-BCR signaling is a compelling candidate as a chemotherapy-independent targeted treatment modality, offering a promising new avenue which could be especially relevant in the management of high-risk pediatric ALL subtypes and providing a foundation for further translational investigation. Our cell line profiling resource is an exciting ongoing effort with significant potential for identification and evaluation of new treatment opportunities and the molecular phenotypes underlying sensitivity. Citation Format: Isabelle R Leo, Frederik Post, Nona Struyf, Xuekang Qi, Luay Aswad, Thao TT Nguyen, Minori Tamai, Koshi Akahane, Katja Pokrovskaja-Tamm, Tom Erkers, Takeshi Inukai, Janne Lehtiö, Rozbeh Jafari. Therapeutic activation of pre-B-cell receptor signaling in high-risk pediatric ALL: exploiting TCF3 and MYC-linked vulnerabilities abstract. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5 (2Suppl): Abstract nr P30.