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SOCS3 inhibits TPO-stimulated, but not spontaneous, megakaryocytic growth in primary myelofibrosis

Leukemia volume 23, pages 1186–1190 (2009)Cite this article

In classical myeloproliferative disorders (MPDs) induced by JAK2V617F, JAK2 exon 12 or MPL W515 mutations, constitutive activation of the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway may confer cytokine hypersensitivity and cytokine-independent growth. In vitro and animal model studies have shown that JAK2V617F may be sufficient to explain the onset of some MPDs such as polycythemia vera (PV). However, phenotypic heterogeneity observed between the classical MPDs may result from an additional increase in JAK/STAT signaling. We hypothesized that alterations in the regulators of JAK2 activity, such as the suppressor of cytokine signaling (SOCS) proteins, may contribute to MPD in addition to JAK2 or MPL mutations.1

The SOCS proteins are potent inhibitors of JAK2 signaling.2 It has been established that SOCS1, SOCS2 and SOCS3 promoters are hypermethylated, thus underexpressed in primary myelofibrosis (PMF).1, 3, 4 We earlier reported that SOCS1 overexpression inhibits spontaneous megakaryocytic growth in PMF,5 but the SOCS1 promoter methylation status in PV compared with PMF presents no difference, suggesting that changes in its expression do not explain MPD heterogeneity.3 In contrast, Fourouclas et al.6 have shown that SOCS3 is hypermethylated in a subset of PMFs, but not in other MPDs. Thus, we investigated the role of SOCS3 promoter hypermethylation in PMF. Our results establish that SOCS3 downregulates thrombopoietin (TPO) induced JAK2 signaling, but has no effect on PMF megakaryocyte spontaneous growth.

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Acknowledgements

This study was supported by grants from the INSERM and the la Ligue Nationale Contre le Cancer ‘équipe labellisée 2007’ and fellowships from the Research Ministry (RC) and INSERM (RB).

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Authors and Affiliations

  1. INSERM, U790, Université Paris 11, Institut Gustave Roussy, Villejuif, France

    R Chaligné, R Besancenot, C Marty, W Vainchenker & S Giraudier

  2. AP-HP, Université Paris12, Laboratoire d’Hématologie, Hôpital Henri Mondor, Créteil, France

    C Tonetti & S Giraudier

  3. AP-HP, Service d’Hématologie Clinique, Hôpital Avicenne et Université Paris XIII, Bobigny, France

    J-J Kiladjian

  4. AP-HP, Unité d’Hématologie et de Transplantation, Hôpital St Louis, Paris, France

    G Socié

  5. UMR CNRS 6101, Service d’Hématologie Clinique, CHU Limoges, France

    D Bordessoule

  6. PRB Henri-Mondor, Hôpital Henri Mondor, Créteil, France

    S Giraudier

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for the FIM (French Intergroup for MPD)

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Correspondence to S Giraudier.

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Chaligné, R., Tonetti, C., Besancenot, R. et al. SOCS3 inhibits TPO-stimulated, but not spontaneous, megakaryocytic growth in primary myelofibrosis. Leukemia 23, 1186–1190 (2009). https://doi.org/10.1038/leu.2009.22

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