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. 2014;13(21):3331-5.
doi: 10.4161/15384101.2014.965061.

Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression

Elena Netchiporouk  1 , Ivan V Litvinov, Linda Moreau, Martin Gilbert, Denis Sasseville, Madeleine Duvic
Affiliations

Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression

Elena Netchiporouk et al. Cell Cycle. 2014.

Abstract

Deregulation of STAT signaling has been implicated in the pathogenesis for a variety of cancers, including CTCL. Constitutive activation of STAT5 and STAT3 was observed in early and late stages of CTCL, respectively. In early stages, IL-2, IL-7 and IL-15 signaling via JAK1 and JAK3 kinases is believed to be responsible for activating STAT5, while in advanced stages development of IL-21 autocrine signaling is thought to be important for STAT3 activation. Recent molecular evidence further suggests that upregulation of STAT5 in early disease stages results in increased expression of oncogenic miR-155 microRNA that subsequently targets STAT4 expression on mRNA level. STAT4 signaling is known to be critical for T helper (Th) 1 phenotype differentiation and its loss results in a switch from Th1 to Th2 phenotype in malignant T cells. During this switch the expression of STAT6 is often upregulated in CTCL. In advanced stages, activation of STAT3 and STAT5 may become completely cytokine-independent and be driven only via constitutively active JAK1 and JAK3 kinases. Further research into the molecular pathogenesis of JAK/STAT signaling in this cancer may enable us to develop effective therapies for our patients.

Keywords: Cutaneous T-Cell Lymphoma (CTCL); Mycosis Fungoides; STAT3; STAT4; STAT5; Sézary Syndrome; and STAT6.

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Figures

Figure 1.
Figure 1.
STAT signaling changes in CTCL. (A) In early disease stages increased IL2RA expression together with augmented IL-2, IL-7 and IL-15 cytokine signaling leads to activation of STAT5, which upon phosphorylation, translocates into the nucleus and upregulates the expression of cell survival genes (Bcl-2 and BCL-x), cell cycle genes (Cyclin D and c-Myc) , Th2 cytokines (IL-4) and miR-155. One of the important functions of miR-155 is to downregulate STAT4 expression. This occurs concomitantly with decreased IL-12 cytokine levels in lesional skin and loss of IL-12 receptor β2 chain expression in malignant T cells all leading to the suppression of Th1 phenotype and switch toward the Th2 phenotype. (B) In advanced disease, in addition to the upregulation in STAT5 signaling, establishment of IL-21 autocrine loop promotes STAT3 activation. Furthermore, in late disease stages STAT5 and STAT3 activation can become completely cytokine-independent being driven by constitutively active JAK1 and JAK3 kinases. CP690550 and AZD9150 inhibitors may be able to block such pathogenic JAK activation in CTCL.
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