Dataset Information

Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma.

ABSTRACT: 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.

Significance

Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.

SUBMITTER: Mundy-Bosse BL

PROVIDER: S-EPMC9414823 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma.

Mundy-Bosse Bethany L BL Weigel Christoph C Wu Yue-Zhong YZ Abdelbaky Salma S Youssef Youssef Y Casas Susana Beceiro SB Polley Nicholas N Ernst Gabrielle G Young Karen A KA McConnell Kathleen K KK Nalin Ansel P AP Wu Kevin G KG Broughton Megan M Lordo Matthew R MR Altynova Ekaterina E Hegewisch-Solloa Everardo E Enriquez-Vera Daniel Y DY Dueñas Daniela D Barrionuevo Carlos C Yu Shan-Chi SC Saleem Atif A Suarez Carlos J CJ Briercheck Edward L EL Molina-Kirsch Hernan H Loughran Thomas P TP Weichenhan Dieter D Plass Christoph C Reneau John C JC Mace Emily M EM Gamboa Fabiola Valvert FV Weinstock David M DM Natkunam Yasodha Y Caligiuri Michael A MA Mishra Anjali A Porcu Pierluigi P Baiocchi Robert A RA Brammer Jonathan E JE Freud Aharon G AG Oakes Christopher C CC

Blood cancer discovery 20220301 2

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 pol ...[more]

PMID: 35247900

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Project description:Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NNKTL) has very unique epidemiological, etiologic, histologic, and clinical characteristics. It is commonly observed in Eastern Asia, but quite rare in the United States and Europe. The progressive necrotic lesions mainly in the nasal cavity, poor prognosis caused by rapid local progression with distant metastases, and angiocentric and polymorphous lymphoreticular infiltrates are the main clinical and histologic features. Phenotypic and genotypic studies revealed that the lymphoma is originated from either NK- or γδ T-cell, both of which express CD56. In 1990, the authors first reported the presence of Epstein-Barr virus (EBV)-DNA and EBV-oncogenic proteins, and EBV has now been recognized to play an etiological role in NNKTL. in vitro studies revealed that a wide variety of cytokines, chemokines, and micro RNAs, which may be produced by EBV-oncogenic proteins in the lymphoma cells, play important roles for tumor progression in NNKTL, and could be therapeutic targets. In addition, it was revealed that the interaction between NNKTL cells and immune cells such as monocytes and macrophages in NNKTL tissues contribute to lymphoma progression. For diagnosis, monitoring the clinical course and predicting prognosis, the measurements of EBV-DNAs and EBV-micro RNAs in sera are very useful. For treatment with early stage, novel concomitant chemoradiotherapy such as DeVIC regimen with local radiotherapy and MPVIC-P regimen using intra-arterial infusion developed with concomitant radiotherapy and the prognosis became noticeably better. However, the prognosis of patients with advanced stage was still poor. Establishment of novel treatments such as the usage of immune checkpoint inhibitor or peptide vaccine with molecular targeting therapy will be necessary. This review addresses recent advances in the molecular understanding of NNKTL to establish novel treatments, in addition to the epidemiologic, clinical, pathological, and EBV features.

Dataset Information

Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma.

Significance

Publications

Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma.

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