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 1

Concurrent ablation of Satb1 and increased expression of Notch1 in mature T cells results in lethal adenopathy.

Options: View larger image (or click on image) Download as PowerPoint
Concurrent ablation of Satb1 and increased expression of Notch1 in matur...
(A) Representative sizes of different organs in CD11cCreSatb1fl/flRosa26N1-ICD mice, mice with CD11cCre-dependent Notch1 (N1-ICD) overexpression alone (CD11cCreRosa26N1-ICD), and mice with CD11cCre-induced ablation of Satb1 alone (CD11cCreSatb1fl/fl). LN, axillary lymph nodes. (B) Survival curve of CD11cCreSatb1fl/flRosa26N1-ICD mice (n = 18), mice with CD11cCre-dependent Notch1 overexpression alone (CD11cCreRosa26N1-ICD) (n = 12), mice with CD11cCre-dependent Satb1 ablation alone (CD11cCreSatb1fl/fl) (n = 10), and mice without CD11cCre (n = 11). Log-rank (Mantel-Cox) test: ****P < 0.0001. (C) Weight of different organs in CD11cCreSatb1fl/flRosa26N1-ICD mice (n = 3–5), CD11cCreRosa26N1-ICD mice (n = 5–7), CD11cCreSatb1fl/fl mice (n = 4–5), or mice without Notch1 overexpression or Satb1 ablation (CD11cCre negative) (n = 7). One-way ANOVA with Tukey’s multiple-comparison test: *P < 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001. (D) Representative hematoxylin and eosin staining of kidneys of CD11cCre-negative mouse (left) versus CD11cCreSatb1fl/flRosa26N1-ICD mice (right).