TY - JOUR
T1 - Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma
AU - Mundy-Bosse, Bethany L.
AU - Weigel, Christoph
AU - Wu, Yue Zhong
AU - Abdelbaky, Salma
AU - Youssef, Youssef
AU - Casas, Susana Beceiro
AU - Polley, Nicholas
AU - Ernst, Gabrielle
AU - Young, Karen A.
AU - McConnell, Kathleen K.
AU - Nalin, Ansel P.
AU - Wu, Kevin G.
AU - Broughton, Megan
AU - Lordo, Matthew R.
AU - Altynova, Ekaterina
AU - Hegewisch-Solloa, Everardo
AU - Enriquez-Vera, Daniel Y.
AU - Dueñas, Daniela
AU - Barrionuevo, Carlos
AU - Yu, Shan Chi
AU - Saleem, Atif
AU - Suarez, Carlos J.
AU - Briercheck, Edward L.
AU - Molina-Kirsch, Hernan
AU - Loughran, Thomas P.
AU - Weichenhan, Dieter
AU - Plass, Christoph
AU - Reneau, John C.
AU - Mace, Emily M.
AU - Gamboa, Fabiola Valvert
AU - Weinstock, David M.
AU - Natkunam, Yasodha
AU - Caligiuri, Michael A.
AU - Mishra, Anjali
AU - Porcu, Pierluigi
AU - Baiocchi, Robert A.
AU - Brammer, Jonathan E.
AU - Freud, Aharon G.
AU - Oakes, Christopher C.
N1 - Publisher Copyright:
©2022 American Association for Cancer Research.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85147813947
U2 - 10.1158/2643-3230.BCD-21-0098
DO - 10.1158/2643-3230.BCD-21-0098
M3 - Article
AN - SCOPUS:85147813947
SN - 2643-3230
VL - 3
SP - 154
EP - 169
JO - Blood Cancer Discovery
JF - Blood Cancer Discovery
IS - 2
ER -