DNA methylation in lymphoma: an opportunity?

Epigenetic mechanisms, including DNA methylation, play an important role in not only the development and maturation of normal cells, but also the development and progression of malignant cells.¹  In this edition of Blood, Arribas et al show that DNA methylation profiling identifies 2 subtypes of splenic marginal zone lymphoma with different clinical and genetic features.²  These findings provide an opportunity to better understand the biology of marginal zone lymphoma and optimize therapy by using demethylating agents to reverse the high-methylation phenotype and thereby target malignant B cells.

Splenic marginal zone lymphoma is an uncommon B-cell malignancy representing ∼8% of all non-Hodgkin lymphomas.³  This disease commonly arises in the context of autoimmune processes or chronic infectious diseases. Previous sequencing studies have identified recurrent mutations in key pathways in this disease, notably NOTCH2 mutations in approximately one-quarter of patients. Furthermore, loss of chromosome 7q31-32 is also frequently seen in marginal zone lymphoma.^4,5  Although many patients have a good prognosis, the outcome of this disease can vary, with some patients having a more aggressive disease course or disease transforming to a more aggressive phenotype. Arribas et al, by performing integrated genome-wide DNA-promoter methylation profiling and comparing this with gene-expression profiling, identified a cluster of patients with high promoter methylation who had a very poor outcome compared with others who had a much lower methylation profile. The prognostic relevance of this profile was tested in a discovery set and subsequently validated in an independent cohort of patients. These findings provide an opportunity for patients with marginal zone lymphoma who have a poor prognosis to be prospectively identified based on their methylation profile.

DNA methylation is an epigenetic mechanism that has been implicated in the pathogenesis of chronic inflammatory diseases as well as malignancies, by regulating the differentiation, apoptosis, proliferation, and activation of different cell types.^6,7  This is achieved through alteration of gene expression and regulation of cellular phenotype. The work by Arribas et al identifies methylation of 3 genes—KLF4, CACNB2, and HTRA1—as most important in defining the high-methylation cohort that is associated with a poor outcome. By integrating the methylation data with paired-gene-expression profiling data, they show an inverse correlation between methylation status and expression levels of these and other genes. They also show, using a functional network analysis, that methylation changes have a direct effect on transcription levels of a variety of key genes in the pathogenesis of marginal zone lymphoma. These include genes with significant roles in the fate and differentiation of cells, in cell communication and signal transduction, and in regulation of apoptosis.

These different methylation profiles in splenic marginal zone lymphoma present a further opportunity to treat patients in the high-methylation cohort with demethylating agents such as decitabine. In this study, the authors found that the use of decitabine could reverse the methylation profile in both cell lines and primary patient specimens. Decitabine has been approved for use in the treatment of patients with myelodysplastic syndromes, including previously treated and untreated, de novo, and secondary myelodysplastic syndrome.⁸  Decitabine has been used to treat patients with lymphoma and chronic lymphocytic leukemia but has shown only modest clinical benefit.⁹  The use of decitabine in patients with splenic marginal zone lymphoma, specifically those with a high methylation profile, may be an opportunity to treat a group of patients who have a poor outcome with standard treatment and yet may be more likely to respond to this agent. The rational use of hypomethylating agents in a cohort of marginal zone lymphoma patients who are most likely to benefit is a potential future treatment approach.