1. ¹Institute of Pathology, Campus Benjamin Franklin, Charité—Universitätsmedizin, Berlin, Germany
2. ²Institute of Functional Genomics, Computational Diagnostics Group, University of Regensburg, Regensburg, Germany

Correspondence: Dr M Hummel, Institute of Pathology, Campus Benjamin Franklin, Charité Universitätsmedizin, Hindenburgdamm 30, Berlin 12200, Germany. E-mail: michael.hummel@charite.de

Received 6 July 2007; Revised 16 December 2007; Accepted 10 January 2008; Published online 7 February 2008.

Abstract

A unique feature of the tumor cells (Hodgkin/Reed-Sternberg (HRS)) of classical Hodgkin lymphoma (cHL) is the loss of their B-cell phenotype despite their B-cell origin. Several lines of evidence suggest that epigenomic events, especially promoter DNA methylation, are involved in this silencing of many B-cell-associated genes. Here, we show that DNA demethylation alone or in conjunction with histone acetylation is not able to reconstitute the B-cell-gene expression program in cultured HRS cells. Instead, combined DNA demethylation and histone acetylation of B-cell lines induce an almost complete extinction of their B-cell-expression program and a tremendous upregulation of numerous Hodgkin-characteristic genes, including key players such as Id2 known to be involved in the suppression of the B-cell phenotype. Since the upregulation of Hodgkin-characteristic genes and the extinction of the B-cell-expression program occurred simultaneously, epigenetic changes may also be responsible for the malignant transformation of cHL. The epigenetic upregulation of Hodgkin-characteristic genes thus plays—in addition to promoter DNA hypermethylation of B-cell-associated genes—a pivotal role for the reprogramming of HRS cells and explains why DNA demethylation alone is unable to reconstitute the B-cell-expression program in HRS cells.