GSE169644
Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma [RNA-seq]
Extranodal natural killer/T cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with very poor clinical outcomes and no effective targeted therapies. Improved understanding of the underlying biology of the disease is critical to design more effective treatment. 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 tumors that demonstrated the most epigenetic immaturity were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited a remarkable degree of genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involved the silencing of hundreds of genes (many involved in NK cell development), and loss of transcription factor binding. To investigate therapeutic targeting of the epigenetic developmental blockade, we treated novel PDX models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reduction of DNA methylation, re-expression of NK cell developmental genes, phenotypic NK cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy targeting the developmental blockade in ENKTL. Overall design: RNA-sequencing was performed on 20 ENKTL tumor samples from derived from FFPE blocks.  Fresh/frozen ENKTL and normal NK samples were analyzed including 21 samples from NK developmental stages, 3 ENKTL, and 18 ENKTL samples derived from PDX mice.