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

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) nonHodgkin's lymphomas (100%), and leukemias (94%) had almost universal methylation of SHP1 and relatively less frequent (o30%) methylation of SOCS1 and SYK; (5) MM and monoclonal gammopathy of unknown significance (MGUS) had infrequent methylation of SHP1 (o20%), 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.

Constitutive STAT5 activation specifically cooperates with the loss of p53 function in B-cell lymphomagenesis

“…We failed to detect decreased expression of these phosphatases between TgSTAT5A* leukemic cells and normal lymphoid cells, indicating that loss of expression of these phosphatases is not responsible for enhanced STAT5 tyrosine phosphorylation in TgSTA-T5A* leukemia. The genes encoding SHPTP1 and SOCS1, two negative regulators of the JAK/STAT pathway, are frequently methylated in human B-cell leukemia/lymphoma (Reddy et al, 2005). However, we failed to detect any defect in SHPTP1 and SOCS1 expression in TgSTAT5A* leukemic cells, indicating that inactivation of these genes is unlikely to be instrumental in STAT5 hyperactivation in STAT5A* (Fleming et al, 2004).…”

Dormant Tumor Cells Develop Cross-Resistance to Apoptosis Induced by CTLs or Imatinib Mesylate via Methylation of Suppressor of Cytokine Signaling 1

“…Here, we observed that dormant tumor cells progressively methylate the SOCS1 gene, ultimately silencing expression. Methylation of the SOCS1 gene has been reported in several human tumors, including lymphoid and myeloid hematologic malignancies (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Our findings suggest a possible role in tumor dormancy.…”

Immunohistochemical detection of tyrosine phosphatase SHP‐1 predicts outcome after radical prostatectomy for localized prostate cancer

“…A large number of studies have been focused on the role of SHP-1 in hematopoietic cells, 13,[34][35][36][37] whereas the role of SHP-1 in epithelial cells and epithelium-derived carcinomas is less well characterized. In hematopoietic cells, SHP-1 has been suggested to contribute to the termination of mitogenic signals of growth factors by dephosphorylating critical phosphorylated molecules.…”