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Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice
Carly M. Harro, … , Lubomir Sokol, Jose R. Conejo-Garcia
Carly M. Harro, … , Lubomir Sokol, Jose R. Conejo-Garcia
Published December 3, 2020
Citation Information: J Clin Invest. 2021;131(3):e135711. https://doi.org/10.1172/JCI135711.
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Research Article Hematology Article has an altmetric score of 68

Methyltransferase inhibitors restore SATB1 protective activity against cutaneous T cell lymphoma in mice

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Abstract

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 protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Therefore, inhibition of methyltransferases that silence SATB1 could address an unmet need for patients with mycosis fungoides/Sézary syndrome, a set of incurable diseases.

Authors

Carly M. Harro, Jairo Perez-Sanz, Tara Lee Costich, Kyle K. Payne, Carmen M. Anadon, Ricardo A. Chaurio, Subir Biswas, Gunjan Mandal, Kristen E. Rigolizzo, Kimberly B. Sprenger, Jessica A. Mine, Louise C. Showe, Xiaoqing Yu, Kebin Liu, Paulo C. Rodriguez, Javier Pinilla-Ibarz, Lubomir Sokol, Jose R. Conejo-Garcia

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Figure 3

Satb1 ablation and Notch activation cooperate to transform postthymic CD8+ T lymphocytes into skin-homing lymphoma cells with phosphorylated Stat5 and cytokine increase.

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Satb1 ablation and Notch activation cooperate to transform postthymic C...
(A) Accumulation of CD3+ T cells in skin of 10-week-old CD11cCreSatb1fl/flRosa26N1-ICD mice compared with single-genotype littermates. Scale bars: 100 μm. (B) Quantitative representation of positive pixel count (PPC) of CD3+ staining of skin from CD11cCreSatb1fl/flRosa26N1-ICD (n = 10), CD11cCreRosa26N1-ICD (n = 8), CD11cCreSatb1fl/fl (n = 8), and CD11cCre-negative mice (n = 8). One-way ANOVA with Tukey’s multiple-comparison test: ***P ≤ 0.001; ****P ≤ 0.0001. (C) Representative Giemsa staining of peripheral blood in the CD11cCreSatb1fl/flRosa26N1-ICD mice. Scale bar: 100 μm. (D) Western blot analysis of protein extracts from GFP+ (Notch1-overexpressing) cells sorted from the bone marrow of CD11cCreSatb1fl/flRosa26N1-ICD and CD11cCreRosa26N1-ICD mice, plus sorted CD8+ T cell splenocytes from wild-type (Cre–) and CD11cCreSatb1fl/fl mice. Representative of 2 independent experiments. (E) Immunopurified CD3+ T cells (2 × 105) were stimulated with 0.5 μg/mL PMA and 1 μg/mL ionomycin in RMP1 with 10% FBS for 4 hours at 37°C. Supernatants were diluted 1:40 and IL-2 was quantified by ELISA (BioLegend) for CD11cCreSatb1fl/flRosa26N1-ICD (n = 6), CD11cCreRosa26N1-ICD (n = 3), and CD11cCre-negative mice (n = 3). One-way ANOVA with Tukey’s multiple-comparison test: ****P ≤ 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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