This proposal describes a 5-year training program to enable the applicant, Dr. Jagan Muppidi, to increase his scientific knowledge, learn new skills in cancer biology and develop an independent research program in lymphoma biology. Dr. Muppidi's primary mentor, Dr. Jason Cyster, is a Professor in the Department of Microbiology and Immunology at UCSF and an Investigator of the Howard Hughes Medical Institute. Dr. Cyster is an internationally recognized immunologist with a long-standing interest in organizational cues involved in the germinal center (GC) reaction. Dr. Muppidi's scientific and career development will be aided by the members of his mentorship committee. Dr. Kevin Shannon, a Professor in the Department of Pediatrics and Molecular Oncology at UCSF, has a strong track record of mentoring physician-scientists and developing novel mouse models of hematopoietic malignancy and is an expert in Ras signaling. Dr. Emmanuelle Passegue, an Associate Professor in the Department of Medicine at UCSF, is an expert in the cues regulating survival and function of hematopoietic stem cells in the bone marrow microenvironment. GC B cell-like diffuse large B cell lymphoma (GCB-DLBCL) and Burkitt Lymphoma (BL) are lymphoid malignancies that are derived from GC B cells. Although GC B cells are normally non-recirculatory and tightly confined to the GC niche, GC-derived lymphomas are systemic diseases and systemic chemotherapy is a mainstay of treatment even in limited stage disease. Little is currently known about what factors are important for supporting dissemination of GC-derived malignancies into circulation and what microenvironmental factors can promote the survival of disease at distant sites. Frequent loss of function mutations in the gene GNA13 (encoding the G-protein Ga13) have been described in GCB-DLBCL and BL. Our recent work has suggested that that disruption of Ga13 signaling may contribute to systemic dissemination of GC-derived malignancy. The overall goal of the proposed research is to understand how loss of GC niche confinement contributes to the development and/or dissemination of germinal center (GC) B cell-derived lymphomas. This goal will be accomplished in two specific aims: 1) Characterize whether loss of GC confinement due to mutation of Ga13 is important for promoting lymphoma development and/or dissemination; 2) Functionally characterize alterations in expression of the Ga13 effector, ARHGEF1 found in GC-derived lymphomas and determine whether loss of this Ga13-effector is sufficient to drive lymphomagenesis. The proposed research may identify therapeutic targets that could be used to generate novel treatment strategies for patients with GC-derived lymphomas. This work may also be useful in identifying patients with GC-derived lymphoma at high risk for developing disseminated disease and therefore require more aggressive front line therapy.
The mechanisms by which lymphomas derived from non-recirculatory GC B cells can disseminate systemically are incompletely defined. The G-protein, Ga13, is frequently lost in GC-derived malignancy. In this proposal, we will elucidate the role of Ga13 signaling in GC-derived lymphomas to understand how its loss might contribute to the development and/or systemic dissemination of lymphoma. Understanding the cues that are important for promoting the systemic dissemination of GC-derived lymphomas may identify therapeutic targets that limit disease in patients.
|Muppidi, Jagan R; Lu, Erick; Cyster, Jason G (2015) The G protein-coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination. J Exp Med 212:2213-22|