Novel pathological mechanisms of B lymphoma development and progression
Creators: name: Jung, Jaeyong
Publisher: name: No Publisher Supplied
Year: 2024

description: B lymphomas are significant health issues both in the US and worldwide. Advances in new targeted therapy and immunotherapy, together with traditional chemotherapy, radiotherapy, surgery, and bone marrow or stem cell transplant, have significantly improved patient survival, but many subtypes of B lymphomas remain incurable. Thus, a better understanding of the pathological mechanisms is required. Various intrinsic signaling pathways of oncogenic mutations in genes such as MYC or TRAF3 drive B cell malignant transformation and lymphoma development. Interestingly, our laboratory recently reported that specific ablation of the adaptor protein TRAF3 from myeloid cells also leads to spontaneous B lymphoma development in mice, suggesting the existence of B cell-extrinsic pathological mechanisms. In an effort to elucidate such novel mechanisms, we found that depletion of commensal bacteria with broad-spectrum antibiotic treatment effectively prevented or substantially inhibited the development and metastasis of spontaneous B lymphomas in two different mouse models. These models include the myeloid cell-specific Traf3-deficient (M-Traf3-/-) mice with diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) and B cell-specific Traf3-deficient (B-Traf3-/-) mice with splenic marginal zone lymphoma (MZL) or B1 lymphoma. Interestingly, we detected commensal bacteria transmigration to the liver in M-Traf3-/- mice but no evidence of transmigration or infection in B- Traf3-/- mice, suggesting that commensal bacteria can promote B lymphoma development and progression even in the absence of transmigration and systemic infection. Although commensal bacteria have been implicated in the carcinogenesis of other human cancers (such as colon, pancreatic, liver, and breast cancers), B lymphocytes are the only cell type of the mammalian body that expresses specific antigen receptors (BCR) and can produce specific antibodies in response to commensal bacterial antigens. Notably, almost all human B lymphomas that demonstrate active BCR signaling and inhibition of this pathway by BTK inhibitors have recently achieved clinical success. In this context, our findings obtained from the two mouse models with B lymphomas led us to test a novel hypothesis that in the absence of infection, commensal bacteria-derived antigens can engage BCR signaling to induce B cell survival, proliferation, or activation, thereby promoting B lymphoma development and progression in genetically predisposed individuals. Indeed, my dissertation research has provided multiple lines of evidence to support this hypothesis, including both in vitro and in vivo data obtained from complementary mouse models and human malignant B cell lines as well as patient samples. Overall, my dissertation research provides novel insights to better understand the pathological mechanisms of B lymphoma development and progression. Importantly, our findings obtained from this study bear significant implications for the development of novel diagnostics and therapeutics to improve early detection, prevention, and treatment for patients with various B lymphomas.