Cutaneous T cell lymphomas (CTCL) are a group of T cell malignancies, which include Mycosis Fungoides (MF) and Sezary Syndrome (SS) and are characterized by proliferation of neoplastic CD4+CD45RO+ T-cells in the upper layers of the skin. Most patients with MF present with early skin stage, defined as superficial patches or plaques affecting a limited areas of skin surface. However a significant subset progresses to advanced skin stage with greater skin surface involvement, development of nodular (tumor) lesions, and high risk of visceral extension. Unlike MF, SS is characterized by a triad of exfoliative erythroderma (a very distinct and diffuse pattern of skin involvement), abundant malignant T-cells in the peripheral blood (PB), and lymphadenopathy. A number of studies have described differential gene expression in MF (skin) and SS (blood) samples to discover tumor-specific biomarkers, however an understanding of the respective cells of origin and their genetic relatedness is still lacking. By performing microarray analysis on highly purified populations of SS T-cells and normal T-cells, we identified a set of non-lymphoid genes (gene signature) that are highly overexpressed (50- fold to 1000-fold) in SS T-cells but are absent in normal T-cells and other hematopoietic cells. Due to a very high signal-to-noise ratio in the PB, these genes have a distinctive advantage as potentially novel blood biomarkers for SS. We also have preliminary evidence that they can be detected in the PB of patients with early and late stage MF, without discernible circulating malignant T-cells. Based on these preliminary data, we hypothesize that a subset of these genes will be consistently detected in the PB of MF patients. The first objective of our work, therefore, is to ascertain the potential role of these genes as MF/SS blood biomarkers by determining prevalence of expression in the PB of a large population of patients with MF/SS seen at the OSUCCC cutaneous lymphoma clinic. We also hypothesize that differential expression of the genes (i.e. type and number of genes expressed, level of expression), will be observed in advanced stage MF versus early stage MF. Our second goal is to perform a nested case control study to identify a progression signature by detecting longitudinal changes in the gene signature in individual patients as they progress from early to advanced stage. We will perform these studies using PB samples from patients with known clinical history banked at the OSUCCC Cancer Center. If this work is successful, we anticipate that the biomarkers will help us to: 1) develop a risk stratification tool for MF/SS, 2) determine the mechanism of upregulation and the biological function of these genes in malignant T-cells, and 3) develop new methods to identify and purify malignant T-cells for further discovery.
Mycosis Fungoides and Sezary Syndrome are two related types of Cutaneous T cell lymphoma (CTCL) that are often difficult to distinguish from other benign chronic skin disorders due to the lack of sensitive and specific markers. Physicians treating patients with MF and SS have two fundamental goals: 1) to accurately and timely make a diagnosis to enhance patient quality of life and survival, and 2) to identify as early as possibl patients with MF whose disease will not respond well to conventional treatment and will proceed to become a life-threatening disease. The experiments proposed here will help us defining the impact of a set of new MF and SS biomarkers that we recently discovered on these two important goals.
|de Silva, Suresh; Wang, Feifei; Hake, Timothy S et al. (2014) Downregulation of SAMHD1 expression correlates with promoter DNA methylation in Sezary syndrome patients. J Invest Dermatol 134:562-5|
|de Silva, Suresh; Hoy, Heather; Hake, Timothy S et al. (2013) Promoter methylation regulates SAMHD1 gene expression in human CD4+ T cells. J Biol Chem 288:9284-92|