Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors

Jyotsna Reddy, Narayan Shivapurkar, Takao Takahashi, Gunjan Parikh, Victor Stastny, Chinyere Echebiri, Katherine Crumrine, Sabine Zöchbauer-Müller, Johannes Drach, Yingye Zheng, Ziding Feng, Steven H. Kroft, Robert W. McKenna, Adi F. Gazdar

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

The perturbations of the cytokine signaling pathway play an important role in lymphoid/hematopoietic tumors. Aberrant promoter methylation is the major mechanism of gene silencing in tumors. We examined 150 lymphoid/hematopoietic tumors or potential premalignant specimens, 55 control specimens and 12 EBV-transformed B lymphoblastoid cultures and 10 lymphoma/leukemia (L/L) or multiple myeloma (MM) cell lines for the methylation (and, in cell lines, of the expression status) of three genes involved in the cytokine signaling pathway. The genes were: SHP1, a protein tyrosine phosphatase; SYK, a protein kinase; and SOCS1, a suppressor of cytokine signaling. Our major findings were: (1) one or more of the three genes was frequently methylated in L/L and MM cell lines and there was good concordance (90-100%) between methylation and loss of gene expression; (2) treatment of L/L cell lines with a demethylating agent resulted in re-expression of SHP1 protein and down-regulation of phosphorylated STAT3 in L/L cell lies; (3) all 55 control specimens and the lymphoblastoid cultures were negative for methylation of the three genes; (4) non-Hodgkin's lymphomas (100%), and leukemias (94%) had almost universal methylation of SHP1 and relatively less frequent (<30%) methylation of SOCS1 and SYK; (5) MM and monoclonal gammopathy of unknown significance (MGUS) had infrequent methylation of SHP1 (<20%), and occasional methylation of SOCS1 and SYK; and (6) comparable methylation frequencies for SOCS1 were observed in MM and MGUS, suggesting that SOCS1 methylation is an early event in MM pathogenesis. At least one gene was methylated in 119 of 130 (93%) of the malignant and 12 of 20 (60%) of the MGUS samples. Our findings demonstrate that the perturbations of cytokine signaling via silencing of these three genes are almost universal in lymphoid/hematopoietic tumors but the patterns of gene methylated for L/L and plasma cell dyscrasias are different.

Original languageEnglish (US)
Pages (from-to)732-736
Number of pages5
JournalOncogene
Volume24
Issue number4
DOIs
StatePublished - Jan 20 2005

Keywords

  • Cytokine signaling pathway
  • Hematopoietic tumors
  • Methylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Reddy, J., Shivapurkar, N., Takahashi, T., Parikh, G., Stastny, V., Echebiri, C., Crumrine, K., Zöchbauer-Müller, S., Drach, J., Zheng, Y., Feng, Z., Kroft, S. H., McKenna, R. W., & Gazdar, A. F. (2005). Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. Oncogene, 24(4), 732-736. https://doi.org/10.1038/sj.onc.1208032