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Chronic Myeloproliferative Disorders

SOCS2: inhibitor of JAK2V617F-mediated signal transduction

Leukemia volume 22, pages 2169–2175 (2008)Cite this article

Abstract

Janus kinase 2 (JAK2)V617F-activating mutations (JAK2mu) occur in myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDSs). Cell lines MB-02, MUTZ-8, SET-2 and UKE-1 carry JAK2V617F and derive from patients with MPD/MDS histories. Challenging the consensus that expression of JAK2V617F is the sole precondition for cytokine independence in class I cytokine receptor-positive cells, two of four of the JAK2mu cell lines were growth factor-dependent. These cell lines resembled JAK2wt cells regarding JAK2/STAT5 activation: cytokine deprivation effected dephosphorylation, whereas erythropoetin or granulocyte colony-stimulating factor induced phosphorylation of JAK2 and STAT5. Cytokine independence correlated with low expression and cytokine dependence with high expression of the JAK/STAT pathway inhibitor suppressor of cytokine signaling 2 (SOCS2) suggesting a two-step mechanism for cytokine independence of MPD cells: (i) activation of the oncogene JAK2V617F and (ii) inactivation of the tumor suppressor gene SOCS2. Confirming that SOCS2 operates as a negative JAK2V617F regulator, SOCS2 knockdown induced constitutive STAT5 phosphorylation in JAK2mu cells. CpG island hypermethylation is reported to promote SOCS gene silencing in malignant diseases. Accordingly, in one of two cytokine-independent cell lines and in two of seven MPD patients, we found SOCS2 hypermethylation associated with reduced promoter access to transcription factors. Our results provide solid evidence that SOCS2 epigenetic downregulation might be an important second step in the genesis of cytokine-independent MPD clones.

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Authors and Affiliations

  1. DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany

    H Quentmeier, R A F MacLeod, S Nagel, S Röhrs, J Romani, M Zaborski & H G Drexler

  2. Department of Mucosal Immunity, Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany

    R Geffers

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

    E Jost

  4. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Medical School Hannover, Hannover, Germany

    M Scherr

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  1. H Quentmeier
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Correspondence to H Quentmeier.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Quentmeier, H., Geffers, R., Jost, E. et al. SOCS2: inhibitor of JAK2V617F-mediated signal transduction. Leukemia 22, 2169–2175 (2008). https://doi.org/10.1038/leu.2008.226

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