Promoter methylation patterns in Richter syndrome affect stem-cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma

Andrea Rinaldi, Afua Adjeiwaa Mensah, Ivo Kwee, Francesco Forconi, Ester M. Orlandi, Marco Lucioni, Valter Gattei, Roberto Marasca, Françoise Berger, Sergio Cogliatti, Franco Cavalli, Emanuele Zucca, Gianluca Gaidano, Davide Rossi, Francesco Bertoni

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Summary: In a fraction of patients, chronic lymphocytic leukaemia (CLL) can transform to Richter 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 H3K27me3 mark and PRC2 targets, as well as for gene targets of TP53 and RB1. 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.

Original languageEnglish
Pages (from-to)194-204
Number of pages11
JournalBritish Journal of Haematology
Volume163
Issue number2
DOIs
Publication statusPublished - Oct 2013

Fingerprint

Lymphoma, Large B-Cell, Diffuse
Methylation
Cell Cycle
Stem Cells
Maintenance
B-Cell Chronic Lymphocytic Leukemia
DNA Methylation
Genes
B-Cell Leukemia
cdc Genes
p53 Genes
Regulator Genes
Genome

Keywords

  • CDKN2A
  • Chronic lymphocytic leukaemia
  • Histological transformation
  • TP53
  • WT1

ASJC Scopus subject areas

  • Hematology

Cite this

Promoter methylation patterns in Richter syndrome affect stem-cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma. / 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.

In: British Journal of Haematology, Vol. 163, No. 2, 10.2013, p. 194-204.

Research output: Contribution to journalArticle

Rinaldi, A, Mensah, AA, Kwee, I, Forconi, F, Orlandi, EM, Lucioni, M, Gattei, V, Marasca, R, Berger, F, Cogliatti, S, Cavalli, F, Zucca, E, Gaidano, G, Rossi, D & Bertoni, F 2013, 'Promoter methylation patterns in Richter syndrome affect stem-cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma', British Journal of Haematology, vol. 163, no. 2, pp. 194-204. https://doi.org/10.1111/bjh.12515
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. / Promoter methylation patterns in Richter syndrome affect stem-cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma. In: British Journal of Haematology. 2013 ; Vol. 163, No. 2. pp. 194-204.
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AU - Forconi, Francesco

AU - Orlandi, Ester M.

AU - Lucioni, Marco

AU - Gattei, Valter

AU - Marasca, Roberto

AU - Berger, Françoise

AU - Cogliatti, Sergio

AU - Cavalli, Franco

AU - Zucca, Emanuele

AU - Gaidano, Gianluca

AU - Rossi, Davide

AU - Bertoni, Francesco

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N2 - Summary: In a fraction of patients, chronic lymphocytic leukaemia (CLL) can transform to Richter 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 H3K27me3 mark and PRC2 targets, as well as for gene targets of TP53 and RB1. 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.

AB - Summary: In a fraction of patients, chronic lymphocytic leukaemia (CLL) can transform to Richter 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 H3K27me3 mark and PRC2 targets, as well as for gene targets of TP53 and RB1. 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.

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