Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR/ABL-negative myeloproliferative disorders.
An acquired autoactivating mutation with a V617F amino-acid substitution in the JAK2 tyrosine kinase is frequently found in BCR/ABL-negative myeloproliferative disorders (MPD). Hypermethylation of CpG islands within gene promoter regions is associated with transcriptional inactivation and represents an important mechanism of gene silencing in the pathogenesis of hematopoietic malignancies. In this study, we determined the DNA methylation status of 13 cancer-related genes in the context of JAK2 mutations in 39 patients with MPD. Genes analyzed for hypermethylation were SOCS-1, SHP-1, E-cadherin, MGMT, TIMP-2, TIMP-3, p15, p16, p73, DAPK1, RASSF1A, RARbeta2 and hMLH1. We found at least one hypermethylated gene in 15/39 MPD patient specimens, and in 6/39 samples aberrant methylation of the negative cytokine regulator SOCS-1 was present. The JAK2V617F mutation was found in 21/39 patients as determined by allele-specific polymerase chain reaction. Hypermethylation of SOCS-1 was observed in 3/21 patients with an autoactivating JAK2 mutation and in 3/18 patients with wild-type JAK2. Our results suggest that epigenetic inactivation of SOCS-1 may be a complementary mechanism to the JAK2V617F mutation in the pathogenesis of MPD that leads to dysregulation of JAK-STAT signal transduction and thus contributes to growth factor hypersensitivity.
Jost
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E
Medizinische Klinik IV, Universitaetsklinikum Aachen, RWTH Aachen, Germany.
do O
N
N
Dahl
E
E
Maintz
C E
CE
Jousten
P
P
Habets
L
L
Wilop
S
S
Herman
J G
JG
Osieka
R
R
Galm
O
O
D019943:Amino Acid Substitution; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D016044:Fusion Proteins, bcr-abl; D005786:Gene Expression Regulation; D020868:Gene Silencing; D052138:Genes, Neoplasm; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000502:physiology; D007951:Leukemia, Myeloid / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D018168:Receptors, Retinoic Acid / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000502:physiology
D018168:Receptors, Retinoic Acid; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C082925:retinoic acid receptor beta; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2