1. ¹Medizinische Klinik IV, Universitaetsklinikum Aachen, RWTH Aachen, Germany
2. ²Institut fuer Pathologie, Universitaetsklinikum Aachen, RWTH Aachen, Germany
3. ³Hematology/Oncology Practice, Wuerselen, Germany
4. ⁴Department of Internal Medicine, St Nikolaus Hospital, Eupen, Belgium
5. ⁵Hematology/Oncology Practice, Aachen, Germany
6. ⁶The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Correspondence: Dr O Galm, Medizinische Klinik IV, Universitaets-klinikum Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail: oliver.galm@post.rwth-aachen.de

Received 10 July 2006; Revised 31 October 2006; Accepted 3 November 2006; Published online 18 January 2007.

Abstract

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, RAR2 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.