Loss of nuclear pro–IL-16 facilitates cell cycle progression in human cutaneous T cell lymphoma

Abstract

Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin lymphomas that affect the skin. The pathogenesis of these conditions is poorly understood. For example, the signaling mechanisms contributing to the dysregulated growth of the neoplastic T cells are not well defined. Here, we demonstrate that loss of nuclear localization of pro-IL-16 facilitates CTCL cell proliferation by causing a decrease in expression of the cyclin dependent-kinase inhibitor p27Kip1. The decrease in p27Kip1 expression was directly attributable to an increase in expression of S-phase kinase-associated protein 2 (Skp2). Regulation of Skp2 is in part attributed to the nuclear presence of the scaffold protein pro-IL-16. T cells isolated from 11 patients with advanced CTCL, but not those from healthy controls or patients with T cell acute lymphocytic leukemia (T-ALL), demonstrated reduction in nuclear pro-IL-16 levels. Sequence analysis identified the presence of mutations in the 5ʹ end of the PDZ1 region of pro-IL-16, a domain required for association of pro-IL-16 with the nuclear chaperone HSC70 (also known as HSPA8). HSC70 knockdown led to loss of nuclear translocation by pro-IL-16 and subsequent increases in Skp2 levels and decreases in p27Kip1 levels, which ultimately enhanced T cell proliferation. Thus, our data indicate that advanced CTCL cell growth is facilitated, at least in part, by mutations in the scaffold protein pro-IL-16, which directly regulates Skp2 synthesis.

A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert-Bazin type) mycosis fungoides

“…This result was somewhat surprising as, in other solid tumours, CDKN1B loss of expression due to promoter methylation is considered a rare event . Moreover, IGF2 and CDKN1B epigenetic silencing could be possible ‘driver’ changes causally involved in cutaneous tumorigenesis, in keeping with recent studies showing that low p27/kip1 levels are very common in CTCLs, depending on nuclear pro–IL‐16 expression . In contrast, CDKN1C/ p57 and RUNX3 , which are often transcriptionally downregulated in tumours via promoter DNA methylation, were invariably unmethylated.…”

Comprehensive analysis of PTEN status in Sézary syndrome

“…46 Interestingly, central memory T lymphocytes express high levels of phosphor-FOXO3a, 47 maintaining in this way low levels of proapoptotic and cell cycle arrest FOXO3a target genes like FAS ligand, Bim, and p27, which are downregulated in SS. [48][49][50] Altogether, this evidence strongly suggests that PTEN may enhance the apoptotic resistance of SS cells via FOXO3a, thus contributing with other genetic hits to their malignant expansion.…”

Regulation of Cellular Processes by Interleukin‐16 in Homeostasis and Cancer

“…It was identified that a loss of nuclear pro‐IL‐16 correlates strongly with loss of CD26 expression and with increasing stage of disease (Richmond et al, ). Further assessment of pro‐IL‐16 in the primary cells identified a sequence mutation, not in the NLS as was detected in the cell line but, in the N terminal region of PDZ1 (Curiel‐Lewandrowski et al, ). This mutation prevented association of pro‐IL‐16 with a nuclear chaperone, heat shock cognate protein 70 (HSC70), thereby preventing subsequent translocation of pro‐IL‐16 to the nucleus.…”