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

Carly M Harro1,2,3, Jairo Perez-Sanz1, Tara Lee Costich1

  • 1Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.

The Journal of Clinical Investigation
|December 3, 2020
PubMed

Insights

Ablating special AT-rich sequence-binding protein 1 (Satb1) in mice caused T cell lymphoma. Silencing of SATB1 via epigenetic repression is key in human Sézary syndrome, suggesting methyltransferase inhibition as a therapeutic target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Cutaneous T cell lymphoma (CTCL) lacks a clear cause and cure.
  • The role of genomic organizers in T cell lymphoma is not fully understood.

Purpose of the Study:

  • To investigate the function of special AT-rich sequence-binding protein 1 (Satb1) in T cell lymphoma development.
  • To explore SATB1 epigenetic regulation in human Sézary syndrome.

Main Methods:

  • Conditional knockout mice were used to ablate Satb1 in T cells.
  • Epigenetic analysis (H3K27/H3K9 trimethylation) and methyltransferase inhibition (SUV39H1/2, EZH2) were performed on human Sézary cells.
  • Cell growth assays compared the efficacy of methyltransferase inhibitors and romidepsin.

Main Results:

  • Satb1 ablation in mice led to malignant transformation of mature T cells into fatal lymphoma.
  • Epigenetic repression of SATB1, mediated by H3K27 and H3K9 trimethylation, was observed in human Sézary syndrome cells.
  • Inhibition of SUV39H1/2 methyltransferases restored SATB1 expression and selectively inhibited Sézary cell growth more effectively than romidepsin.

Conclusions:

  • Satb1 acts as a tumor suppressor in T cells by restraining Stat5 phosphorylation and skin-homing receptor expression.
  • Epigenetic silencing of SATB1 is a critical mechanism in Sézary syndrome pathogenesis.
  • Targeting methyltransferases that silence SATB1 offers a potential therapeutic strategy for mycosis fungoides/Sézary syndrome.
Keywords:
HematologyLymphomas

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