SATB1 in Malignant T Cells

Abstract

Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis.

Divergent SATB1 expression across human life span and tissue compartments

“…In peripheral tissues, the dysregulation of SATB1 expression is involved in various human cancers. Tumor stage‐dependent downregulation of SATB1 by miR‐155 was reported in cutaneous T‐cell lymphomas . Overexpression of SATB1 has been reported in cutaneous anaplastic lymphoma driven by the SATB1 promoter methylation state .…”

“…SATB1 has been shown to be dysregulated in human T-cell lymphoma. 8,9 Given its role in regulating PD-1, 22 a T-cell exhaustion marker, 13 SATB1 could be an attractive molecule to understand PD-1 regulation in current cancer immunotherapeutic approaches which aim to reverse T-cell exhaustion by PD-1 blockade. In this study, we have characterized the level of SATB1 expression in human T-cell differentiation subsets across different human tissues in pediatric and adult donors.…”

“…Tumor stage-dependent downregulation of SATB1 by miR-155 was reported in cutaneous T-cell lymphomas. 8 Overexpression of SATB1 has been reported in cutaneous anaplastic lymphoma driven by the SATB1 promoter methylation state. 9,29 These contrasting findings suggest a Figure 6.…”

“…In human cancer studies, SATB1 is thought to be important in promoting tumor growth and invasion, including breast cancers, prostate cancers, colorectal cancers, or pancreatic cancers . Dysregulated SATB1 expression was further linked to the pathogenesis of T‐cell lymphoma …”

“…7 Dysregulated SATB1 expression was further linked to the pathogenesis of Tcell lymphoma. 8,9 SATB1 originally was described to be expressed in Tcell populations, especially in the thymus. 1,2,10 Essential roles of SATB1 in organizing temporal and spatial expression of genes were shown for T-cell development in murine thymi after the generation of SATB1-null mice.…”