These data identify a new mechanism of immune evasion in CTCL and suggest that the CD80-CD152 axis may become a therapeutic target in this type of lymphoma.
We used a heterologous system in which mutant human CD28 was expressed on primary murine T cells deficient in CD28 to ascertain how specific mutations identified in a genetic screen of patients with cutaneous T cell lymphoma affected normal T cell function.
We performed G-banding/spectral karyotyping, extensive gene expression analysis, TP53 sequencing in the 11 patient-derived <i>HTLV-1<sup>+</sup></i> (MJ and Hut102) vs. <i>HTLV-1<sup>-</sup></i> (Myla, Mac2a, PB2B, HH, H9, Hut78, SZ4, Sez4 and SeAx) CTCL cell lines.
Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53.
Taken together, our findings suggest that USP2 stabilizes Mdm2 which antagonizes pro-apoptotic activity of p53 and possibly contributes to therapeutic resistance in CTCL.
Driver genes identified using MutSigCV include POT1, which has not been previously reported in CTCL; and TP53 and DNMT3A, which were also identified consistent with previous reports.
These alterations were accompanied by increased forkhead box O3 (FoxO3) in several cell lines and increased nuclear p53, as well as acetylated p53 in wtp53 MyLa CTCL line.
Furthermore, we analysed the TP53 mutation status in CTCL cell lines and highly purified tumour cells from patients with SS by mRNA and DNA sequencing.
We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL.
We analysed a panel of 24 samples of mycosis fungoides (MF), the most frequent manifestation of cutaneous T-cell lymphoma (CTCL), for beta-catenin, p53 and p63 protein expression by immunohistochemistry.
We analysed a panel of 24 samples of mycosis fungoides (MF), the most frequent manifestation of cutaneous T-cell lymphoma (CTCL), for beta-catenin, p53 and p63 protein expression by immunohistochemistry.
Because of its high positive rates in high grade lesions, the p53 expression showed positive correlation with histologic grade; however, the Ki-67 labeling index did not correlate with the histologic grade in CTCL.
We have previously demonstrated that the resistance of CTCL to apoptosis correlates with decreased expression of death receptors such as FAS, and that methotrexate functions as an epigenetic regulator that reestablishes the susceptibility of CTCL to extrinsic pathway apoptosis.