Histone acetylation and DNA demethylation of B cells result in a Hodgkin-like phenotype.
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.
Ehlers
A
A
Institute of Pathology, Campus Benjamin Franklin, Charité-Universitätsmedizin, Berlin, Germany.
Oker
E
E
Bentink
S
S
Lenze
D
D
Stein
H
H
Hummel
M
M
D000107:Acetylation; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006689:Hodgkin Disease / Q000235:genetics / Q000473:pathology*; D010641:Phenotype
D006657:Histones