Nelson, Geoffrey M
Mayo Clinic
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Citations 2
IRF4 Promotes Immune Evasion and Shapes the Tumor Microenvironment in Follicular Lymphoma
Dasari, Surendra , Wenzl, Kerstin , Nelson, Geoffrey M. , Guzman, Emmanuel Contreras , Wang, Zhiquan , Chartier, Loïc , Yang, Zhi-Zhang , Villasboas, José C. , Olson, Joshua , Mukherjee, Prithviraj , Tang, Xinyi , Gysbers, Brianna J. , Zakrzewski, Johannes L. , King, Rebecca L. , Huet, Sarah , Tesson, Bruno , Nowakowski, Grzegorz S. , Pasqualucci, Laura , Novak, Anne J. , Ansell, Stephen M. , Contreras Guzman, Emmanuel , Bhardwaj, Vaishali , Tang, Xinyi , Gysbers, Brianna J , Zakrzewski, Johannes L , King, Rebecca L , Huet, Sarah , Tesson, Bruno , Maurer, Matthew , Morschhauser, Franck , Nowakowski, Grzegorz S , Adelman, Karen , Singh, Harinder , Pasqualucci, Laura , Shlomchik, Mark , Novak, Anne J , Ansell, Stephen M , Mondello, Patrizia , Villasboas, Jose Caetano , Yang, Zhi-Zhang , Nelson, Geoffrey M , Bhardwaj, Vaishali , Maurer, Matthew J. , Morschhauser, Franck , Mondello, Patrizia , Wang, Zhiquan
Blood Cancer Discovery | July 16, 2025 | Volume: 6 | Issue: 6 | Pages: 623-645
Abstract Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules while promoting the expression of cytokines that antagonize T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms. Significance: We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.
TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence
Wu, Gongwei , Yoshida, Noriaki , Liu, Jihe , Xiong, Yuan , Heavican‐Foral, Tayla B. , Mandato, Elisa , Nelson, Geoffrey M. , Yang, Lu , Chen, Renee , Jones, M. , Roshal, Mikhail , Zhang, Yanming , Xu, Ran , Jain, Salvia , Leahy, Catharine, Jones, Kristen L. , Stevenson, Kristen E. , Galasso, Natasha, Ganesan, Nivetha , Chang, Tiffany , Wu, Wenchao, Louissaint, Abner , Debaize, Lydie , Cin, Paola Dal , Chan, Wing C. , Sui, Shannan J. Ho , Ng, Samuel Y., Chen, Chun‐Wei , Weinstock, David M. , Zhang, Xiaoyang , Xiong, Yuan , Nelson, Geoffrey M , Yang, Lu , Donovan, Katherine A , Jones, Marcus K , Zhang, Yanming , Xu, Ran , Nirmal, Ajit J , Jain, Salvia , Ganesan, Nivetha , Chang, Tiffany , Dal Cin, Paola , Ho Sui, Shannan J , Feldman, Andrew L , Horwitz, Steven M , Adelman, Karen , Fischer, Eric S , Chen, Chun-Wei , Weinstock, David M , Brown, Myles , Heavican, Tayla B., Liu, Huiyun , Yoon, Hojong , Feldman, Andrew L. , Horwitz, Steven M. , Brown, Myles
Science Translational Medicine | September 20, 2023 | Volume: 15 | Issue: 714 | Pages: No page available
Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)—histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63 -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.