ABSTRACT
The underlying molecular pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive, but considerable progress has been made during the past decade with the application of novel molecular techniques. Malignancies are characterized by a series of acquired genetic or epigenetic abnormalities affecting specific genes that control critical cellular functions such as apoptosis, proliferation, and differentiation as well as genome integrity. Such genes can be dysregulated through a combination of mechanisms including mutation, heterozygous or homozygous deletion, and gene amplification. Dysregulation may also occur via fusion of a gene with a powerful promotor such as the IgH gene in the t(9;14) of Burkitt’s lymphoma or the creation of a novel fusion gene as a consequence of a chromosomal translocation such as the NPM-ALK fusion gene characteristic of the t(2;5) translocation found in systemic CD30+ anaplastic large cell lymphoma.1 Such chromosomal translocations are often tumor specific and may represent either a fundamental pathogenetic abnormality or underlying genomic instability that contributes to the cumulative rate of mutations.2 Importantly, these disease-specific cytogenetic abnormalities are now the focus for the development of tumor-specific therapy, with very encouraging results, as seen in chronic myeloid leukemia with tyrosine kinase inhibitors.3 Epigenetic abnormalities can also lead to dysregulation of genes through different mechanisms, including hypermethylation of CpG-rich sites within promotor sequences of genes producing transcriptional silencing, generalized hypomethylation of DNA, which may cause aberrant expression of specific genes, and deacetylation of histone proteins, affecting chromatin structure and, consequently, gene transcription. Such abnormalities are attractive therapeutic targets, and there is now consid-
erable interest in the development of phase I/II trials assessing novel therapies that have been shown to reverse these epigenetic changes in tumor cells.
