A11
Cross-species screens and investigation of UPS vulnerabilities in high grade lymphoma
Project Summary
Malignant relapsing lymphoma remains a major source of morbidity and mortality and therefore it is of utmost importance to advance our understanding of the dynamic regulation of lymphoma proteomes and signal transduction networks to uncover novel therapeutic vulnerabilities. Ubiquitin genes regulating ubiquitin mediated/dependent protein degradation, altered intracellular localization or signaling play decisive roles in these processes. We will employ genetic engineering and screening technologies in human cell culture systems in vitro as well as in novel mouse models in vivo to systematically characterize and interrogate ubiquitin gene functions in lymphoma biology and responses to currently applied chemotherapies. Lymphomas heavily rely on cell-extrinsic cues for survival and expansion, which is why we put a strong emphasis on obligate lymphoma extrinsic input.
Through cross-species genetic analyses of ubiquitin genes, we identified candidate mediators of mouse lymphomagenesis and maintenance of human lymphoma cells in co-culture systems, with a particular focus on putative functions in the responses to standard chemotherapy. We propose to mechanistically investigate the functions of these candidates in lymphoma biology and to systematically profile ubiquitin genes in lymphoma to identify and characterize novel key players in lymphoma biology and therapy by addressing two main aims:
Aim 1: Cross-species mechanistic assessment of ubiquitin gene candidates as vulnerability in lymphoma
Aim 2: Functional screening of ubiquitin genes for roles in oncogenic programs, T cell activation and drug responses
