Abstract 1841: Venetoclax rewires Notch signaling to drive resistance in North American adult T-cell leukemia/lymphoma.

Purpose: North American Adult T-cell leukemia/lymphoma (NA-ATLL) is an aggressive HTLV-1-associated T-cell malignancy with median survival of less than 2 years. NA-ATLL cases are distinct from those in endemic regions like Japan and exhibit a correlation with poor prognosis and therapeutic resistance. Interferon-alpha/Zidovudine, when combined with other chemotherapy regimens, has shown efficacy in acute and chronic malignancies. We previously showed that Venetoclax induces mitochondrial apoptosis in NA-ATLL; however, resistance inevitably emerges despite initial sensitivity. As limited epidemiologic data delay ATLL research, our center accomplishes one of the nation’s first cohorts, with ∼150 cases annually, predominantly among Caribbean-descent patients. In this study, the use of Venetoclax-treated patient-derived NA-ATLL cells led to prominent Notch pathway activation, highlighting a key adaptive resistance mechanism. Methods: Preclinically, patient-derived NA-ATLL cell lines (Pt-4a, 5a, 6a, 15a) along with Japanese patient-derived ATLL cell lines [ATL43Tb(−)] (J-ATLL) were treated with Venetoclax. RNA-seq identified adaptive survival pathways. Clinically, several patients with aggressive subtypes of NA-ATLL (Shimoyama types: lymphomatous and acute) were treated with Venetoclax-based treatment at our Institution. Results: Preclinical: Both NA-ATLL and J-ATLL cells responded heterogeneously to Venetoclax. In responsive lines, Venetoclax-treated cells enhanced apoptotic priming with caspase-3/PARP-1 activation, and reduced HTLV-1 HBZ and Tax expression whereas non-responders showed minimal effect, while ferroptosis was excluded. BH3 profiling confirmed NA-ATLL has unique apoptotic priming compared to J-ATLL. RNA-seq revealed robust induction of NOTCH1/2, DLL1/4, JAG1/2, and canonical targets HES1. Noteworthy, Venetoclax also upregulated the Fringe glycosylation genes (LFNG, MFNG, RFNG), which augment Notch receptor responsiveness, indicating a glycan-optimized Notch activation program that supports survival under BCL-2 inhibition. Clinical: NA-ATLL patients received Venetoclax-based combinations across multiple therapy lines. Mutation profiling (TP53, NOTCH1) by NGS was correlated with outcomes. Notably, the Venetoclax-based regimes (PEG-IFN + Biktarvy + VEN) produced durable complete responses, with patients remaining alive beyond 95 and 234 days at data cutoff. Conclusion: Venetoclax shows a significant effect in NA-ATLL both at preclinical and clinical settings, but emerging adaptive Notch signaling activation represents a crucial resistance mechanism. Our study supports evaluating Notch-directed agents (γ-secretase inhibitors/Nirogacestat) in combination with Venetoclax to overcome therapeutic resistance and improve outcomes in NA-ATLL. Citation Format: Ankit Tanwar, Salman Sadullah Usmani, Sovira Chaudhry, Aditi Shastri, Marina Konopleva, Murali Janakiram, Ali Bazarbachi, B. Hilda Ye, Xingxing Zang, Amit Verma, R. Alejandro Sica. Venetoclax rewires Notch signaling to drive resistance in North American adult T-cell leukemia/lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1841.