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

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

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Figure 5

Sézary cells, but not other malignant lymphocytes, consistently exhibit SATB1 downregulation.

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Sézary cells, but not other malignant lymphocytes, consistently exhibit ...
(A) Expression of SATB1 in the indicated populations of malignant cells in the bone marrow of patients with T-LGL (n = 7) or T-PLL (n = 6), compared with SATB1 expression in CD8+ (T-LGL) or CD4+ (T-PLL) T cells activated with anti-CD3/anti-CD28 beads for 48 hours. Gated on live CD45+CD3+ CD4+ or CD8+ T cells. FMO, fluorescence minus one. (B) SATB1 downregulation in bone marrow Sézary cells (n = 3). (C) SATB1 downregulation in nonactivated peripheral blood Sézary cells (n = 11) compared with normal donor CD4+ T cells. (D) Log-transformed fold-change values of SATB1 MFI levels of malignant cells over normal CD4+ or CD8+ PBMCs for T-LGL CD4+ bone marrow (BM) (n = 5), T-PLL CD4+ BM (n = 7), T-PLL CD8+ BM (n = 6), Sézary CD4+ BM (n = 3), and Sézary CD4+ PBMCs (n = 11). Two-tailed Student’s t test: *P < 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001.