Relevance of ubiquitin dependent proteolysis in Diffuse Large B-cell lymphoma
Perelman School of Medicine at the University of Pennsylvania
Project Term: July 1, 2022 - June 30, 2027
The goal of this proposal is to investigate the significance of genes of the ubiquitin proteasome system (UPS) that are mutated in Diffuse Large B-cell Lymphoma (DLBCL). Our studies leverage the expertise in the molecular modeling of the UPS in the pathogenesis of DLBCL utilizing mouse models, patient derived xenotransplant (PDX) and cell lines. Our goal is the understanding of how genetic mutations contribute to disease development, progression and therapeutic outcome.
B-Cells are cells in the immune system that help protect the body from infections and other diseases. B-Cell lymphoma is a type of blood cancer that occurs when B-cells start to divide faster than they should or live longer than they are supposed to leading to a dramatic increase in the number of B-cells in the body. There is still little understanding of how gene mutations in B-cells are responsible for causing the abnormal growth of B-cells. In this proposal, we are investigating regulation of the gene KLHL6, which normally blocks the growth of B-cells. KLHL6 is referred to as a “tumor suppressor” gene and it functions to prevent B-cells from uncontrolled growth. However, KLHL6 has been identified as one of the most frequently mutated genes in patients with B-cell lymphoma suggesting that mutations in KLHL6 may be an important driver of B-cell lymphomas. In our studies, we have found the mechanism that control KLHL6 function, allowing us to regulate if not block the abnormal growth of B-cells. All together, this proposal will not only provide important biological insights into the understanding of how B-cell lymphomas develop, but will also assess the rational for “personalized therapy” of patients harboring mutations in KLHL6.