Role of KLHL6 inactivation in mature B-cell malignancies

Project Summary Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma accounting for about 32,000 new cases per year and leading to death in over 40% of cases. This proposal seeks to investigate the biological significance of KLHL6, a gene mutated in mature B-cell cancers, with DLBCL displaying the highest rate of mutations. KLHL6 assembles into a functional CULLIN-RING Ubiquitin ligase (CRL) complex and cancer-associated mutations inhibit KLHL6 interaction to CULLIN3, resulting in loss of activity to transfer ubiquitin chains. In this proposal, we investigate KLHL6 as a master regulator and tumor suppressor of the NOTCH signaling. An investigation of the cell autonomous and drug resistance in murine model of DLBCL as well as patient derived DLBLC xenotransplants will be pursed. Building up on our data, the central hypothesis of this proposal is that deregulation of the KLHL6 function is crucial to lymphomagenesis and impacts therapy. Thus, we aim in modeling loss of Khll6 in a mouse model of DLBCL (Aim1) and we will study how impairment of the NOTCH pathway impacts the therapeutic efficacy of B-cell receptor inhibition in DLBCL (Aim2). Overall, this proposal investigates the mechanisms of DLBCL pathogenesis and treatment. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin ligase glues for the treatment of hematologic diseases has made the Ubiquitin pathway a bona fide target for cancer therapeutics. Thus, defining how novel E3 ligases function at a molecular level and investigating their role in inflammation is critical in order to develop more specific therapeutic avenues.