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

Authors :
Christopher C. Oakes
Aharon G. Freud
Jonathan E. Brammer
Robert A. Baiocchi
Pierluigi Porcu
Anjali Mishra
Michael A. Caligiuri
Yasodha Natkunam
David M. Weinstock
Fabiola Valvert Gamboa
Emily M. Mace
John C. Reneau
Christoph Plass
Dieter Weichenhan
Thomas P. Loughran
Hernan Molina-Kirsch
Edward L. Briercheck
Carlos J. Suarez
Atif Saleem
Shan-Chi Yu
Carlos Barrionuevo
Daniela Dueñas
Daniel Y. Enriquez-Vera
Everardo Hegewisch-Solloa
Ekaterina Altynova
Matthew R. Lordo
Megan Broughton
Kevin G. Wu
Ansel P. Nalin
Kathleen K. McConnell
Karen A. Young
Gabrielle Ernst
Nicholas Polley
Susana Beceiro Casas
Youssef Youssef
Salma Abdelbaky
Yue-Zhong Wu
Christoph Weigel
Bethany L. Mundy-Bosse
Publication Year :
2023
Publisher :
American Association for Cancer Research (AACR), 2023.

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

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....0c189c71003f69be17421be2c363d3ce