Hypermethylation of the suppressor of cytokine signalling-1 (SOCS-1) in myelodysplastic syndrome.
Transcriptional silencing because of hypermethylation is now recognised to be a hallmark of human tumours. In contrast to acute myeloid leukaemia (AML), comparably little is known about aberrant methylation in myelodysplastic syndrome (MDS), a heterogeneous clonal stem cell disorder with a risk of transformation into secondary AML of up to 30%. Recent evidence demonstrates that suppressor of cytokine signalling SOCS-1, a negative regulator of cytokine pathways, may act as a tumour suppressor gene, and inactivation because of hypermethylation was shown in various malignancies. Employing a newly developed quantitative real-time polymerase chain reaction-based methylation assay we analysed, for the first time, SOCS-1 methylation in MDS and found disease-specific hypermethylation in 27 of 86 MDS patients (31%). Demethylation experiments provided direct evidence that aberrant methylation of SOCS-1 induces transcriptional silencing in myeloid cells. In addition, by analysing the expression of signal transducers and activators of transcription (STAT)-induced genes we provide for the first time evidence that the activity of the Janus kinase/STAT pathway is increased in primary patient samples showing SOCS-1 hypermethylation.
Brakensiek
Kai
K
Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany.
Länger
Florian
F
Schlegelberger
Brigitte
B
Kreipe
Hans
H
Lehmann
Ulrich
U
D000208:Acute Disease; D002454:Cell Differentiation; D019175:DNA Methylation; D015536:Down-Regulation; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014407:Tumor Cells, Cultured
D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011505:Protein-Tyrosine Kinases