B cell intrinsic RANK signaling in multiple myeloma pathogenesis

• Applicant: Dr. Maike Buchner
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516923543

Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, have been implicated in the pathogenesis of B-cell malignancies, including Chronic Lymphocytic Leukemia (CLL) and Multiple Myeloma (MM). Previous research on the relevance of RANK/RANKL in MM has largely focused on its role in shaping the bone marrow niche and activating osteoclasts, which is important for the disease progression. However, anti-RANKL treatment reduces MM progression in preclinical models and a role of B cell intrinsic RANK expression in MM pathogenesis is not yet defined. We have preliminary data showing that constitutive activation of RANK signaling together with TCL1 expression in B cells promotes an MM-like disease in mice, with several clinical features of the human disease. Based on these data, we now plan to evaluate the role of B cell intrinsic RANK signaling in the development and progression of murine and human MM in the project proposed in this grant application. In Aim 1, we will identify the signaling alterations induced by TCL1 and RANK activation in B cells and analyze the effects of TCL1 and RANK activation on B cell development and differentiation in vitro and in vivo. In Aim 2, we will investigate the pathogenesis of MM using our new mouse model by assessing transcriptional changes in plasma cells and bone microenvironment of TCL1-RANK mice at different time points during disease progression. In addition, we will determine the extent to which our TCL1-RANK myeloma can serve as a preclinical model for testing novel treatments in an immunocompetent setting. Finally, in Aim 3 of this project, we will investigate the effects of blocking the RANK/RANKL pathway in MM and use genetic and drug screens to identify potential vulnerabilities of RANK-deficient/RANKL-deprived MM cells. We will therefore employ our novel TCL1-RANK driven myeloma model to discover the molecular mechanisms by which TCL1 and RANK signaling cooperate to induce myeloma pathogenesis. We will determine to which extent B cell-intrinsic RANK signaling impacts human MM cell behavior and evaluate whether treatment with anti-RANKL antibody denosumab, currently used to prevent bone resorption in myeloma patients with bone disease, renders myeloma cells vulnerable to other treatment modalities for potential combination treatments.

• DFG Programme: Research Grants