197 Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of disease progression in cutaneous T cell lymphoma

Abstract

DNA hydroxymethylation at the 5 position of cytosine (5-hmC) is a product of the ten-eleven translocation (TET) family of DNA hydroxylases. Accumulating pieces of evidence showed that loss of 5-hmC is critical for various biological and pathological processes. However, its expression and function in cutaneous T cell lymphoma remain largely unknown. Here, with a large cohort of patients, we report that loss of 5-hmC is an epigenetic hallmark of cutaneous T cell lymphoma, with diagnostic and prognostic implications. Immunohistochemistry staining on 91 mycosis fungoides (MF) cases display a significant decrease of 5-hmC staining in CD4+ T cells, compared to benign inflammatory dermatoses, including lupus erythematosus (N=15), lichen planus (N=15), and psoriasis (N=12). 5-hmC staining level is further decreased with disease progression and demonstrates remarkable loss of staining in the large cells of large cell transformed MF cases, regardless of the CD30 positivity. Furthermore, 5-hmC decreases are correlated with poorer overall survival in our patient cohort. Compared to healthy CD4+ T cells, 5-hmC levels also decreased in 9 CTCL cell lines. Pharmacological augment of global 5hmC with L-ascorbic acid [L-AA] and 2-phospho-L-ascorbic acid (P-AA) in CTCL cell lines lead to a remarkable 5-hmC accumulation and induce specific apoptosis in CTCL cell lines, as well as primary CTCL cells. In conclusion, 5-hmC is an epigenetic marker of disease progression in MF. Reversing 5-hmC levels in MF may serve as a novel therapeutic regimen in cutaneous T cell lymphoma.