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Chronic Myeloproliferative Disorders

Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR/ABL-negative myeloproliferative disorders

Leukemia volume 21, pages 505–510 (2007)Cite this article

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, RARβ2 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.

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Acknowledgements

We thank Sandra Mellen, Lucia Vankann, Ramona Latton, Inge Losen and Ingeborg Wiegand for expert technical assistance. This work was supported by grants from the Rheinisch-Westfaelische Technische Hochschule Aachen (START program) and the Deutsche Krebshilfe. JGH is a paid consultant to and receives research support from OncoMethylome Sciences. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Authors and Affiliations

  1. Medizinische Klinik IV, Universitaetsklinikum Aachen, RWTH Aachen, Germany

    E Jost, N do Ó, S Wilop, R Osieka & O Galm

  2. Institut fuer Pathologie, Universitaetsklinikum Aachen, RWTH Aachen, Germany

    E Dahl

  3. Hematology/Oncology Practice, Wuerselen, Germany

    C E Maintz

  4. Department of Internal Medicine, St Nikolaus Hospital, Eupen, Belgium

    P Jousten

  5. Hematology/Oncology Practice, Aachen, Germany

    L Habets

  6. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore,, MD, USA

    J G Herman

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Jost, E., do Ó, N., Dahl, E. et al. Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR/ABL-negative myeloproliferative disorders. Leukemia 21, 505–510 (2007). https://doi.org/10.1038/sj.leu.2404513

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