Aberrant JAK-STAT pathway confers resistance to the HDAC inhibitor chidamide in Natural Killer/T-cell lymphoma through chromatin remodeling
Natural Killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with poor prognosis and limited therapeutic options. Here, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating relapsed/refractory NKTL patients, achieving an overall response rate of 39.3%, with 17.9% complete response rate. However, the clinical response to chidamide remains variable as more than half of the patients exhibit primary resistance, limiting its utility in NKTL treatment. To unravel the resistance mechanisms of chidamide, we performed integrative transcriptomic and chromatin profiling of sensitive and resistant NKTL cells. Our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. Collectively, our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL. Overall design: 1. Chromatin immunoprecipitation sequencing (ChIP-Seq) for H3K27ac and H3K4me3  was performed in two resistant cell lines (HANK1 and SNK6) and two sensitive cell lines (KHYG1 and MEC04) to chidamide. 2. RNA-seq was performed in three resistant cell lines (SNT8, SNK6 and HANK1) and three sensitive cell lines (KHYG1, MEC04 and NK92)  to chidamide. 3.RNA-seq for HANK1 treated with DMSO, tofacitinib or ruxolitinib was performed (duplicate).