SE-induced drug resistance can be either JAK-dependent or -independent. (A) Heatmaps showing cytokines secreted by PBMCs derived from SS4 after 24, 48, and 72 hours of treatment with 2 nM romidepsin in the presence or absence of SE. (B) Heatmap showing cytokine expression across the cell types identified in the CITE-seq data set from SS17 after 36 hours of treatment with 2 nM romidepsin in the presence or absence of SE. Expression is calculated as log1p transformed unique transcripts per million $log1p(CytokineUMIscelltypeTotalUMIssample/106)$⁠. (C-D) Representative flow cytometric plots (C; SS13) and quantification (D) of percentage of viable malignant cells from PBMCs of 7 patients with SS (SS4, SS5, SS6, SS8, SS12, SS13, and SS14) treated with 2 nM romidepsin for 72 hours in the presence or absence of cytokines (IL-2, IL-4, IL-7, and IL-15). Statistical significance was assessed by ordinary 1-way ANOVA followed by Tukey multiple comparison test. ∗∗∗∗P < .0001. (E-H) Representative flow cytometric plots (SS8 [E]; SS10 [G]) and quantifications of percentage of viable malignant cells from PBMCs of patients with SS treated with 2 nM romidepsin for 72 hours in the presence or absence of SE and JAK inhibitor (1 μM tofacitinib) of patients exhibiting JAK-independent (E-F) (n = 3 [SS8, SS12, and SS13]) or JAK-dependent (G-H) (n = 2 [SS4 and SS10]) resistance being induced by the presence of SE. (E) PBMCs from SS8 treated in the presence of cytokines (IL-2, IL-4, IL-7, and IL-15) as well as SRC inhibitor (2 μM A-419259). DMSO, dimethyl sulfoxide; NK cells, natural killer cells.