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.
View: Text | PDF
Research Article Hematology Article has an altmetric score of 68

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

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

×

Figure 2

Satb1 ablation transforms the Notch-dependent expansion of CD8+ T cells into a full-blown CD4+CD8+ T cell lymphoma.

Options: View larger image (or click on image) Download as PowerPoint
Satb1 ablation transforms the Notch-dependent expansion of CD8+ T cells...
(A) Notch-overexpressing (GFP+) cells in the peripheral blood of 10-week-old CD11cCreSatb1fl/flRosa26N1-ICD mice are CD56–TCRγδ–CD3+ T cells. (B) An initial population of GFP+CD8+ T cells overexpressing Notch1 progressively transforms into CD4+CD8+ T cells at advanced stages of malignant progression, with quantitative representation of CD3+GFP+ T cells from peripheral blood. (C) Progressive accumulation of CD4+CD8+ T cells in the peripheral blood of CD11cCreSatb1fl/flRosa26N1-ICD mice. (D) Progressive expansion of CD8+ T cells, but not CD4+CD8+ malignant lymphocytes, in Notch-overexpressing mice without Satb1 ablation. (E) Quantitative representation of progressive accumulation of CD4+CD8+, CD4+, and CD8+ T cells in CD11cCreSatb1fl/flRosa26N1-ICD mice (n = 4–12), CD11cCreRosa26N1-ICD (n = 4–6), and CD11cCre-negative mice (n = 6–9). Two-tailed Student’s t test (B and E): **P ≤ 0.01.