Abstract 5755: TP63 fusions drive enhancer rewiring, lymphomagenesis, and dependence on EZH2

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.5755-5755
• Main Authors: Wu, Gongwei, Yoshida, Noriaki, Liu, Jihe, Zhang, Xiaoyang, Xiong, Yuan, Heavican-Foral, Tayla, Liu, Huiyun, Nelson, Geoffrey, Yang, Lu, Chen, Renee, Donovan, Katherine, Jones, Marcus, Roshal, Mikhail, Zhang, Yanming, Xu, Ran, Nirmal, Ajit, Jain, Salvia, Leahy, Catharine, Jones, Kristen, Stevenson, Kristen, Galasso, Natasha, Ganesan, Nivetha, Chang, Tiffany, Wu, Wen-Chao, Louissaint, Abner, Debaize, Lydie, Yoon, Hojong, Cin, Paola Dal, Chan, Wing Chan, Sui, Shannan Ho Sui Ho, Ng, Samuel, Feldman, Andrew, Horwitz, Steven M., Meyerson, Mathew, Adelman, Karen, Fischer, Eric, Chen, Chun-Wei, Weinstock, David, Brown, Myles
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-5755

Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas. Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending on cohorts. The function and mechanisms of TP63 rearrangements and TP63 fusion proteins in tumorigenesis are poorly understood. As a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to understand how TP63 fusions contribute to tumorigenesis and to translate the findings into novel therapeutic options for these patients. Here, we demonstrated that TP63 fusions are essential for the propagation of T-cell lymphomas (TCLs). Knockdown of TP63 fusions with specific shRNAs in TCL cell lines harboring TP63 fusions suppressed both cell growth in vitro and tumor growth in vivo. Retroviral expression of TBL1XR1-TP63, the most common TP63 fusion, conferred cytokine independence in Ba/F3 cells, consistent with its role as an oncogene. To investigate the role of TP63 fusions in T- and B-cell lymphomagenesis, we engineered a CAG-Loxp-Stop-Loxp-TBL1XR1-TP63 conditional knock-in mouse model and crossed with hCD2-Cre mice. This results in expression beginning during early lymphoid development. As observed in patients, transgenic mice developed multiple subtypes of both T- and B-cell lymphoma. To define the effects and mechanisms of TP63 fusions within T cells, we performed CRISPR scanning, transcriptomic, epigenomic, and proteomic analyses. Our data showed that domains within both the N-terminal TBL1XR1 and C-terminal TP63 portions contribute to the function of this fusion. We found that the N-terminal component of TP63 fusions interacts with components of the NCOR/SMRT complex. At the same time, the C-terminal portion of TP63 (which recapitulates the deltaN-p63 isoform expressed in some carcinomas) interacts with the enhancer modifier KMT2D and its complex members. TBL1XR1-TP63 binds to a novel distal enhancer to drive MYC expression, and thus upregulates the expression of the histone H3K27 methylase EZH2. Finally, we assessed whether EZH2 is a vulnerability of TP63-rearranged lymphomas. We found that knockdown of EZH2 in TP63-rearranged lines significantly impaired cell growth, as did treatment with the EZH2 and 1 dual inhibitor valemetostat. Valemetostat, which is now be