Hypomethylation of CD30 CpG islands with aberrant JunB expression drives CD30 induction in Hodgkin lymphoma and anaplastic large cell lymphoma.
High expression of CD30 and JunB is the hallmark of malignant cells in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). Ligand-independent signaling by CD30 induces JunB, which activates the CD30 promoter, stabilizing CD30 expression and supporting the survival of Hodgkin-Reed-Sternberg (H-RS) and ALCL cells. Here we show for the first time CpG islands encompassing 60 CpG dinucleotides, located in the core promoter, exon 1 and intron 1 of CD30 gene. Analysis of the methylation status of CD30 CpG islands in H-RS, ALCL and unrelated cell lines reveals an inverse relationship between the extent of CD30 CpG methylation and CD30 expression. CD30 CpG islands of H-RS and ALCL cell lines are rarely methylated. Methylation of the CD30 promoter decreases CD30 induction and JunB action on the demethylated CD30 promoter enhances CD30 induction. CD30 and JunB are strongly expressed in H-RS and ALCL cells, whereas they are not expressed in nonmalignant lymphocytes in which CD30 CpG islands are rarely methylated. We conclude that constitutive action of aberrantly expressed JunB on hypomethylated CD30 CpG islands of lymphocytes triggers CD30 induction and initiates activation of the JunB-CD30-JunB loop, essential to the pathogenesis of HL and ALCL.
Watanabe
Mariko
M
Department of Hematology, School of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan.
Ogawa
Yuji
Y
Itoh
Kinji
K
Koiwa
Tukasa
T
Kadin
Marshall E
ME
Watanabe
Toshiki
T
Okayasu
Isao
I
Higashihara
Masaaki
M
Horie
Ryouichi
R
D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D018899:CpG Islands; D004247:DNA; D019175:DNA Methylation; D017931:DNA Primers; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D017730:Ki-1 Antigen / Q000096:biosynthesis*; D017728:Lymphoma, Large-Cell, Anaplastic / Q000276:immunology*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D017730:Ki-1 Antigen; D016755:Proto-Oncogene Proteins c-jun; D004247:DNA