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Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. Oncogene 2005 Jan 20;24(4):732-6

Date

12/08/2004

Pubmed ID

15580314

DOI

10.1038/sj.onc.1208032

Scopus ID

2-s2.0-19944432663   53 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 downregulation of phosphorylated STAT3 in L/L cell lines; (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.

Author List

Reddy J, Shivapurkar N, Takahashi T, Parikh G, Stastny V, Echebiri C, Crumrine K, Z??chbauer-M??ller S, Drach J, Zheng Y, Feng Z, Kroft SH, McKenna RW, Gazdar AF

Author

Steven Howard Kroft MD Chair, Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Line, Tumor
Cytokines
DNA Methylation
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Hematologic Neoplasms
Humans
Intracellular Signaling Peptides and Proteins
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases
RNA, Messenger
STAT3 Transcription Factor
Signal Transduction
Trans-Activators