Analysis and Therapeutic Targeting Non-proteolytic Protein Ubiquitination in Diffuse Large B Cell Lymphoma

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 DESCRIPTION (provided by applicant): My doctoral and post-doctoral training have collectively focused on using multidisciplinary genetic, biochemical and immunological approaches to dissect the function of protein ubiquitination in signaling and diseases. With the experience, knowledge and skills I gained from my doctoral and post-doctoral training, I am now prepared to start as an independent scientist to continue my research of signal transduction pathways in hematologic malignancies, with a particular interested in ubiquitin-mediated signaling and immune regulatory pathways in lymphoma pathogenesis. My future independent research will build upon my post-doctoral studies of the critical role of both the proteolytic and nonproteolytic protein ubiquitination system in lymphoma pathogenesis. My current objective is to apply multidisciplinary approaches to investigate the role of protein ubiquitination systems in the pathogenesis of lymphoid malignancies. The proposed K22 proposal in this application directly builds upon my post-doctoral training, and the publication/results from this proposal will serve as a foundation of my future grant application. My long-term career goal/objective is to direct new treatment strategies for human disease like lymphoma by targeting protein ubiquitination system. I believe my research will broaden our fundamental understanding of immune regulatory mechanisms in lymphomagenesis and open up new avenues for drug development. The proposed study entitled "Analysis and Therapeutic Targeting Non-proteolytic Protein Ubiquitination in Diffuse Large B Cell Lymphoma" will address the importance of cIAP1/2 E3 ligases in the pathogenesis of Activated B Cell-like subtype of Diffuse Large B Cell Lymphoma (ABC DLBCL), and that SMAC mimetics could be a novel therapeutic strategy in this disease. In this study, the requirement of cIAP1/2 their enzymatic activities in chronic active B Cell Receptor (BCR) signaling pathway mediated NF-B activation will be defined by CRISPR/CAS9 genetic knockout approach. Biochemically, the detailed mechanism of how cIAP1/2 E3 ligases mediate BCR signaling will be established. Lastly, the therapeutic potential of SMAC mimetic birinapant in ABC DLBCL will be exploit in human lymphoma lines and in various DLBCL mice xenograft models in vivo. Moreover, a high-throughput small molecule screen will be used to identify other drugs that exhibit synergistic toxicity for ABC DLBCL cells when combined with birinapant, to increase the response rates and durability.