TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence

Author:

Wu Gongwei12ORCID,Yoshida Noriaki1ORCID,Liu Jihe3,Zhang Xiaoyang145ORCID,Xiong Yuan67ORCID,Heavican-Foral Tayla B.1,Mandato Elisa1,Liu Huiyun1,Nelson Geoffrey M.78ORCID,Yang Lu9ORCID,Chen Renee9,Donovan Katherine A.67ORCID,Jones Marcus K.1ORCID,Roshal Mikhail10,Zhang Yanming10ORCID,Xu Ran1ORCID,Nirmal Ajit J.1ORCID,Jain Salvia11ORCID,Leahy Catharine1,Jones Kristen L.1,Stevenson Kristen E.1,Galasso Natasha12,Ganesan Nivetha12ORCID,Chang Tiffany12ORCID,Wu Wen-Chao1,Louissaint Abner113,Debaize Lydie1,Yoon Hojong67,Dal Cin Paola14ORCID,Chan Wing C.15,Ho Sui Shannan J.3ORCID,Ng Samuel Y.116,Feldman Andrew L.17ORCID,Horwitz Steven M.12ORCID,Adelman Karen47ORCID,Fischer Eric S.67ORCID,Chen Chun-Wei9ORCID,Weinstock David M.14ORCID,Brown Myles12ORCID

Affiliation:

1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

2. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

3. Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.

4. Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.

5. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

7. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

8. Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.

9. Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA 91016, USA.

10. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

11. Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

12. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

13. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.

14. Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA.

15. Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA.

16. Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

17. Division of Hematopathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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