Abstract 5177: Modeling 6q deletion and MYD88L265P-driven B-cell lymphomas in mice reveals early lymphomagenesis mechanisms and identifies the putative cell of origin

Abstract Chromosomal aberrations often represent early events in cancer development and might play a critical role in establishing malignant clones. Large chromosomal deletions typically involve the loss of multiple cooperating tumor suppressor genes, which makes it challenging to study their contribution to cancer pathogenesis. Recent genomic studies have identified the MYD88L265P mutation and chromosome 6q deletion as frequent alterations in Waldenstrom’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL). These genetic abnormalities are considered to be key drivers of oncogenic NF-κB signaling and are also observed in diffuse large B-cell lymphoma (DLBCL). Previous studies, including our own, have demonstrated that neither human MYD88L265P nor murine Myd88L252P mutations alone are sufficient to induce neoplastic transformation in mouse models. Chr6q deletion, containing multiple genes involved in B cell biology, might constitute a critical “second hit” necessary for sustaining MYD88L265P-induced signaling. This study aimed to elucidate the roles of MYD88L265P and Chr6q (syntenic to murine Chr10q) deletion in B-cell lymphoma pathogenesis. We generated the following genetically engineered mouse models: Myd88L252P/+;Cd19Cre/+, 10q+/-;Cd19Cre/+ and Myd88L252P/+;10q+/-;Cd19Cre/+. We have observed spontaneous development of low- and high-grade B cell lymphomas in aged cohorts of 10q+/-;Cd19Cre/+ and Myd88L252P/+;10q+/-;Cd19Cre/+ mice. Pathological analysis showed an expansion of lymphoplasmacytic B220- SOX5+ PAX5+ IgM+ B cells, which infiltrated the bone marrow, spleen and lymph nodes. To investigate the progression of B-cell changes during premalignant and malignant stages, we performed scRNA-seq on murine lymphoid organ samples. There was an early clonal expansion of B1 and memory B cells, potentially representing lymphoma precursor cells. Later on, these populations were replaced by larger cells frequently positive for Ki67, IRF4, and IgM, suggesting a transition from a low-grade WM-like disease to a high-grade DLBCL. Both early- and late-stage lymphomas exhibited elevated expression of therapeutic targets, including Bcl2, Ms4a1, Btk and Hck, offering potential avenues for intervention and therapy response studies. Additionally, profound alterations were observed in the T-cell compartment, with an increased frequency of PD1+ LAG3+ TIM3+ cells, suggesting immunotherapy targets that merit further validation. The mouse models provide valuable platforms for investigating the mechanistic roles of these genetic alterations and testing therapeutic strategies. In the future, we plan to validate the models as preclinical tools for studying MYD88 and Chr6q deletion-driven lymphomagenesis. This project was supported by the Robert A. Kyle Career Development Award from the IWMF and NIH grant R01CA273123. Citation Format: Filip Garbicz, Johany Penailillo, Senthilkumar Muthiah, Fernanda Cuevas, Tuyet Nguyen, Elisa Mandato, Eleonora Calabretta, Tomasz Sewastianik, Elena Ivanova, Aisha Saldanha, Moataz Noureddine, Rafael Irizarry, Margaret A. Shipp, Zachary Hunter, Steven P. Treon, Ruben D. Carrasco. Modeling 6q deletion and MYD88L265P-driven B-cell lymphomas in mice reveals early lymphomagenesis mechanisms and identifies the putative cell of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5177.