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JAK/STAT signaling in hematological malignancies

Oncogene volume 32, pages 2601–2613 (2013)Cite this article

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Abstract

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is central to signaling by cytokine receptors, a superfamily of more than 30 transmembrane proteins that recognize specific cytokines, and is critical in blood formation and immune response. Many of those receptors transmit anti-apoptotic, proliferative and differentiation signals, and their expression and functions are critical for the formation of blood lineages. Several cancers, including blood malignancies, have been associated with constitutive activation of members of the STAT family, which normally require JAK-mediated tyrosine phosphorylation for transcriptional activation. More recently, human myeloproliferative neoplasms were discovered to be associated with a unique acquired somatic mutation in JAK2 (JAK2 V617F), rare exon 12 JAK2 mutations, or thrombopoietin receptor mutations that constitutively activate wild-type JAK2. Prompted by these observations, many studies have explored the possibility that JAKs, cytokine receptors, or other components of the JAK/STAT pathway are mutated or upregulated in several hematological malignancies. This has been observed in certain pediatric acute lymphoblastic leukemias and adult T-cell lymphoblastic leukemias, and overexpression of JAK2 seems to be important in Hodgkin lymphoma. Here we discuss the nature and respective contribution of mutations dysregulating the JAK/STAT pathway in hematological malignancies and present examples in which such mutations drive the disease, contribute to the phenotype, or provide a survival and proliferative advantage. JAK inhibitors are making their way into the therapeutic arsenal (for example, in myelofibrosis), and we discuss the possibility that other hematological diseases might benefit from treatment with these inhibitors in combination with other agents.

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Acknowledgements

Financial support for medical editorial and graphic design assistance was provided by Novartis Pharmaceuticals. We thank Matthew Hoelzle PhD, Daniel Hutta, PhD and Isabelle Plo PhD for their assistance with this manuscript.

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Authors and Affiliations

  1. INSERM, UMR 1009, Hematopoïèse Normale et Pathologique, Villejuif, France

    W Vainchenker

  2. Institut Gustave Roussy, UMR 1009, Villejuif, France

    W Vainchenker

  3. Université Paris-Sud, UMR 1009, Villejuif, France

    W Vainchenker

  4. Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium

    S N Constantinescu

  5. de Duve Institute, Université Catholique de Louvain, Brussels, Belgium

    S N Constantinescu

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  1. W Vainchenker
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  2. S N Constantinescu
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Correspondence to S N Constantinescu.

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There is potential conflict of interest. Both WV and SNC have participated in ad-hoc Scientific Advisory Boards at Novartis related to JAK inhibitors.

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Vainchenker, W., Constantinescu, S. JAK/STAT signaling in hematological malignancies. Oncogene 32, 2601–2613 (2013). https://doi.org/10.1038/onc.2012.347

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  • DOI: https://doi.org/10.1038/onc.2012.347

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