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Promoter methylation patterns in R ichter syndrome affect stem‐cell maintenance and cell cycle regulation and differ from de novo diffuse large B ‐cell lymphoma
Author(s) -
Rinaldi Andrea,
Mensah Afua Adjeiwaa,
Kwee Ivo,
Forconi Francesco,
Orlandi Ester M.,
Lucioni Marco,
Gattei Valter,
Marasca Roberto,
Berger Françoise,
Cogliatti Sergio,
Cavalli Franco,
Zucca Emanuele,
Gaidano Gianluca,
Rossi Davide,
Bertoni Francesco
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12515
Subject(s) - dna methylation , methylation , biology , cell cycle , cancer research , gene , epigenetics , diffuse large b cell lymphoma , microbiology and biotechnology , stem cell , lymphoma , gene expression , genetics , immunology
Summary In a fraction of patients, chronic lymphocytic leukaemia ( CLL ) can transform to R ichter syndrome ( RS ), usually a diffuse large B –cell lymphoma ( DLBCL ). We studied genome‐wide promoter DNA methylation in RS and clonally related CLL ‐phases of transformed patients, alongside de novo DLBCL (of non‐germinal centre B type), untransformed‐ CLL and normal B ‐cells. The greatest differences in global DNA methylation levels were observed between RS and DLBCL , indicating that these two diseases, although histologically similar, are epigenetically distinct. RS was more highly methylated for genes involved in cell cycle regulation. When RS was compared to the preceding CLL ‐phase and with untransformed‐ CLL , RS presented a higher degree of methylation for genes possessing the H 3 K 27me3 mark and PRC 2 targets, as well as for gene targets of TP 53 and RB 1. Comparison of the methylation levels of individual genes revealed that OSM , a stem cell regulatory gene, exhibited significantly higher methylation levels in RS compared to CLL ‐phases. Its transcriptional repression by DNA methylation was confirmed by 5‐aza‐2′deoxycytidine treatment of DLBCL cells, determining an increased OSM expression. Our results showed that methylation patterns in RS are largely different from de novo DLBCL . Stem cell‐related genes and cell cycle regulation genes are targets of DNA methylation in RS .