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

Mundy-Bosse B.L.; Weigel C.; Wu Y.-Z.; Abdelbaky S.; Youssef Y.; Casas S.B.; Polley N.; Ernst G.; Young K.A.; McConnell K.K.; Nalin A.P.; Wu K.G.; Broughton M.; Lordo M.R.; Altynova E.; Hegewisch-Solloa E.; Enriquez-Vera D.Y.; Dueñas D.; Barrionuevo C.; Yu S.-C.; Saleem A.; Suarez C.J.; Briercheck E.L.; Molina-Kirsch H.; Loughran T.P.; Weichenhan D.; Plass C.; Reneau J.C.; Mace E.M.; Gamboa F.V.; Weinstock D.M.; Natkunam Y.; Caligiuri M.A.; Mishra A.; Porcu P.; Baiocchi R.A.; Brammer J.E.; Freud A.G.; Oakes C.C. · Blood Cancer Discovery (2022) · DOI: 10.1158/2643-3230.bcd-21-0098

Resumen

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.