biostudies-literatureHarro CMAmerican Cancer SocietyNational Cancer InstituteNCI NIH HHS135711https://www.ebi.ac.uk/biostudies/studies/S-EPMC7843215biostudies-literatureUnknown131(3)Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence-binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored prThe Journal of clinical investigationMethyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice.PMC7843215T32CA009140T32 CA009140P30 CA010815P30-CA076292R01 CA157664R01CA240434,R01CA157664,R01CA124515,) CA076292R01 CA240434U01 CA200495R01 CA124515P30 CA076292R01 CA184185Pinilla-Ibarz JShowe LCChaurio RABiswas SLiu KHarro CMMandal GConejo-Garcia JRAnadon CMSprenger KBMine JAPayne KKRigolizzo KERodriguez PCPerez-Sanz JCostich TLYu XSokol LfalseMethyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice.Cutaneous T cell lymphoma (CTCL) has a poorly understood etiology and no known cure. Using conditional knockout mice, we found that ablation of the genomic organizer special AT-rich sequence-binding protein 1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. Notably, methyltransferase-dependent epigenetic repression of SATB1 was universally found in human Sézary syndrome, but not in other peripheral T cell malignancies. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition) restored pr2021-01-01T00:00:00Z2021 Feb2026-06-04T03:13:14.768Z2022-02-09T18:06:47.843ZS-EPMC78432153327060610.1172/JCI13571110.1172/jci135711