Abstract Background: Lymphoma progression is shaped by dynamic interactions between malignant B cells and the tumor microenvironment, generating marked transcriptional and functional heterogeneity. To define mechanisms driving this adaptive evolution, we developed a transplantable oncogene-driven lymphoma model enabling controlled tracking of clonal evolution, transcriptional remodeling, and functional adaptation across serial tumor passages. Methods: Primary tumors from transgenic lymphoma-bearing mice were serially propagated into syngeneic hosts, generating early (P0), intermediate (P2), and advanced (P4) stages. Single-cell transcriptomics, CNV-inference (inferCNV), and pathway-level modeling (Seurat/Scanpy, GSVA, Enrichr, DrugBank-based prediction) were used to define malignant and microenvironmental evolution and emerging vulnerabilities. Results: Serial propagation produced progressive transcriptional diversification consistent with malignant evolution. P0 tumors exhibited proliferative activation and metabolic priming, whereas P4 tumors developed immunosuppressive, angiogenic, and stress-adaptive programs mirroring hallmarks of advanced human B-cell lymphoma. A key finding was a unified stress-survival module in P4, marked by hypoxia-responsive, UPR-related, and metabolically rewired pathways, alongside reduced proliferative dependence. Sex-specific pathway biases including cytokine/chemokine signaling and metabolic checkpoint usage also emerged. Drug-response inference identified passage-specific vulnerabilities, with P4 showing heightened sensitivity to inhibitors of oxidative-stress buffering, lipid metabolism, and UPR nodes. Future Directions: Multiparametric flow cytometry, immunohistochemistry, and spatial profiling are underway to validate lineage reprogramming, CNV-based malignant classifications, and pathway activation states. Conclusions: Malignant progression in this model is driven by iterative transcriptional reprogramming and functional adaptation shaped by microenvironmental selection. P4 most accurately recapitulates transcriptomic and functional features of advanced disease, making it an optimal preclinical platform for studying therapeutic resistance and identifying emergent vulnerabilities in aggressive B-cell lymphoma. Citation Format: Bandish Kapadia, Anirban Roychodhury, Forum Kayastha, Won Sok Lee, Nahid Nanaji, Jolene windle, Ronald B. Gartenhaus. Dynamic transcriptional remodeling and functional adaptation drive malignant progression in 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 5571.
Kapadia et al. (Fri,) studied this question.