https://scholars.lib.ntu.edu.tw/handle/123456789/633285
標題: | Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma | 作者: | Mundy-Bosse, Bethany L Weigel, Christoph Wu, Yue-Zhong Abdelbaky, Salma Youssef, Youssef Casas, Susana Beceiro Polley, Nicholas Ernst, Gabrielle Young, Karen A McConnell, Kathleen K Nalin, Ansel P Wu, Kevin G Broughton, Megan Lordo, Matthew R Altynova, Ekaterina Hegewisch-Solloa, Everardo Enriquez-Vera, Daniel Y Dueñas, Daniela Barrionuevo, Carlos SHAN-CHI YU Saleem, Atif Suarez, Carlos J Briercheck, Edward L Molina-Kirsch, Hernan Loughran, Thomas P Weichenhan, Dieter Plass, Christoph Reneau, John C Mace, Emily M Gamboa, Fabiola Valvert Weinstock, David M Natkunam, Yasodha Caligiuri, Michael A Mishra, Anjali Porcu, Pierluigi Baiocchi, Robert A Brammer, Jonathan E Freud, Aharon G Oakes, Christopher C |
公開日期: | 1-三月-2022 | 卷: | 3 | 期: | 2 | 來源出版物: | Blood cancer discovery | 摘要: | Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/633285 | ISSN: | 26433230 | DOI: | 10.1158/2643-3230.BCD-21-0098 |
顯示於: | 病理學科所 |
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