TY - JOUR
T1 - Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors
AU - Reddy, Jyotsna
AU - Shivapurkar, Narayan
AU - Takahashi, Takao
AU - Parikh, Gunjan
AU - Stastny, Victor
AU - Echebiri, Chinyere
AU - Crumrine, Katherine
AU - Zöchbauer-Müller, Sabine
AU - Drach, Johannes
AU - Zheng, Yingye
AU - Feng, Ziding
AU - Kroft, Steven H.
AU - McKenna, Robert W.
AU - Gazdar, Adi F.
N1 - Funding Information:
*Correspondence: AF Gazdar, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-8593, USA; E-mail: adi.gazdar@utsouthwestern.edu Supported by Grant 5U01CA8497102 from Early Detection Research Network (EDRN), National Cancer Institute, Bethesda, MD, USA Received 11 December 2003; revised 14 June 2004; accepted 21 June 2004; published online 6 December 2004
PY - 2005/1/20
Y1 - 2005/1/20
N2 - 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.
AB - 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.
KW - Cytokine signaling pathway
KW - Hematopoietic tumors
KW - Methylation
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U2 - 10.1038/sj.onc.1208032
DO - 10.1038/sj.onc.1208032
M3 - Article
C2 - 15580314
AN - SCOPUS:19944432663
SN - 0950-9232
VL - 24
SP - 732
EP - 736
JO - Oncogene
JF - Oncogene
IS - 4
ER -