While two decades of cancer genetics research have been instrumental in cataloging common mutations across diverse tumors, a substantial gap persists in the functional characterization of these variants compared to our knowledge of their mere presence in tumors. This disparity is particularly pronounced for mutated proteins in rare tumors. This project will investigate the role of one such protein, INO80, in two cancer types: diffuse large B cell lymphomas (DLBCL) and the rare hepatosplenic gamma-delta T cell lymphoma (HSTL). INO80 forms the core of a chromatin remodeling complex and is recurrently mutated in these malignancies, with up to 20% of all HSTL cases containing mutated INO80. However, the functional consequences of INO80 mutations on chromatin maintenance and tumor progression remain unknown. This study will focus on understanding the effects of INO80 mutations, exploring their impact on immune cell dysfunction, genomic stability, metabolism, and lymphomagenesis. The proposal outlines a systematic approach, including functional assays, metabolic profiling, and the creation of preclinical models, including the first mouse model for HSTL, to unravel the complexities of INO80 dysfunction and its potential as a therapeutic target in lymphoid malignancies. The ultimate goal is to provide insights into novel therapeutic strategies, especially for refractory/relapsed DLBCL and the highly lethal HSTL, addressing a critical unmet need in cancer treatment.