TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence Journal Article
| Authors: | Wu, G.; Yoshida, N.; Liu, J.; Zhang, X.; Xiong, Y.; Heavican-Foral, T. B.; Mandato, E.; Liu, H.; Nelson, G. M.; Yang, L.; Chen, R.; Donovan, K. A.; Jones, M. K.; Roshal, M.; Zhang, Y.; Xu, R.; Nirmal, A. J.; Jain, S.; Leahy, C.; Jones, K. L.; Stevenson, K. E.; Galasso, N.; Ganesan, N.; Chang, T.; Wu, W. C.; Louissaint, A.; Debaize, L.; Yoon, H.; Dal Cin, P.; Chan, W. C.; Ho Sui, S. J.; Ng, S. Y.; Feldman, A. L.; Horwitz, S. M.; Adelman, K.; Fischer, E. S.; Chen, C. W.; Weinstock, D. M.; Brown, M. |
| Article Title: | TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence |
| Abstract: | 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. |
| Keywords: | genetics; mouse; animal; animals; mice; transcription initiation; transcription factor; transcription factors; oncogenes; disease model; oncogene; tumor suppressor proteins; cell nucleus; disease models, animal; tumor suppressor protein; transcriptional activation; tp63 protein, human; transcription factor ezh2; corepressor protein; ezh2 protein, human; enhancer of zeste homolog 2 protein; co-repressor proteins; humans; human |
| Journal Title: | Science Translational Medicine |
| Volume: | 15 |
| Issue: | 714 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2023-09-20 |
| Start Page: | eadi7244 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.adi7244 |
| PUBMED: | 37729434 |
| PROVIDER: | scopus |
| PMCID: | PMC11014717 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
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