Mature B-cell neoplasms are the fifth most common neoplasm in both males and females. They arise from B- cells that have entered germinal centers and display great heterogeneity at the clinical and genetic levels. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin ligase inhibitors, lenalinomide for the treatment of multiple myeloma and B-cell lymphomas 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 B-cell malignancies remains a major research imperative in order to develop more specific therapeutic avenues. KLHL6 is a gene of unknown function that is mutated in mature B-cell malignancies such as chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. We have demonstrated that KLHL6 is an E3 ubiquitin ligase and cancer-associated mutations inactivate its catalytic activity. The goals of this research proposal are to define the molecular and cellular functions of KLHL6 with regards substrate degradation and analyze the effects of KLHL6-loss in vivo. Our central hypothesis is that KLHL6 is novel tumor suppressor that may contribute to the pathogenesis of DLBCL and MM by regulating cell proliferation, differentiation and survival.
The completion of this proposal will lead to a better understanding of ubiquitin-based regulation of lymphoid disease progression. Defining the molecular mechanism that links ubiquitin signaling pathway with protein degradation and mRNA decay and establishing the importance of such regulation in hematologic cancers will be critical for generating effective personalized therapeutic approaches.
|Choi, Jaewoo; Lee, Kyutae; Ingvarsdottir, Kristin et al. (2018) Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2. Nat Cell Biol 20:586-596|