Discussion
NKTL, tumor, H3Y41, PTCL
DISORDER, REGRESSION, DISEASE, TUMOR
In the current management of NKTL, a substantial proportion of patients still experience treatment failures, and salvage options are severely limited. Increasing evidence suggests that PTCL is characteristically an epigenetic disorder, with several HDAC inhibitors receiving regulatory approvals for the treatment of relapsed/refractory disease. Here, we conducted the first focused trial of chidamide, an oral HDAC inhibitor, in relapsed/refractory NKTL. Chidamide induced durable tumor regression, with a complete response rate of 18% and a partial response rate of 21%. Compared with other HDAC inhibitors, chidamide is the first selective oral HDAC inhibitor to show effective and increased immunomodulatory effects and convenient administration [We further found that aberrant JAK-STAT signaling contributes to primary resistance to chidamide, and inhibiting this oncogenic pathway can resensitize resistant NKTL cells to chidamide. We have previously demonstrated the prevalence of JAK-STAT pathway alterations in NKTL and discovered frequent Interestingly, we found that JAK-STAT signaling mediates resistance to chidamide through chromatin remodeling of enhancer elements. We demonstrated that drug resistance to chidamide was correlated with chromatin remodeling alterations, which could be reversed by targeting the JAK-STAT pathway. Enhancer but not promoter alterations were significantly correlated with the response to chidamide in NKTL. In addition, STAT motifs were enriched at gained enhancers over lost enhancers, which was consistent with the enrichment of JAK-STAT target genes in resistant cells. Previous studies have demonstrated that the JAK-STAT pathway can regulate chromatin accessibility and influence the chromatin landscape through different mechanisms. For example, JAK2 can directly phosphorylate Tyr41 in histone H3 (H3Y41), preventing the binding of heterochromatin protein 1α (HP1α) with chromatin and destabilizing heterochromatin in hematopoietic cells [Importantly, chromatin-mediated drug resistance is often reversible, as demonstrated by JAK-STAT inhibitor reprogramming of the chromatin state from a resistant to a sensitive state. JAK-STAT inhibition suppresses H3K27ac marks of JAK-STAT target genes, such as Furthermore, JAK-STAT target genes can also serve as predictive or therapeutic biomarkers of chidamide resistance. Frequent overexpression of TNFRSF8 (CD30) in NKTL has been reported previously [