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JAK/STAT signaling in hematological malignancies

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Vainchenker, W. Constantinescu, Stefan N. [UCL]

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.

Document type Article de périodique (Journal article)
Access type Accès restreint
Publication date 2013
Language Anglais
Journal information "Oncogene : including Oncogene Reviews" - Vol. 32, no.21, p. 2601-2613 (2013)
Peer reviewed yes
Publisher Nature Publishing Group ((United Kingdom) London)
issn 0950-9232
e-issn 1476-5594
Publication status Publié
Affiliation UCL - SSS/DDUV - Institut de Duve
Links
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Bibliographic reference Vainchenker, W. ; Constantinescu, Stefan N.. JAK/STAT signaling in hematological malignancies. In: Oncogene : including Oncogene Reviews, Vol. 32, no.21, p. 2601-2613 (2013)
Permanent URL http://hdl.handle.net/2078.1/132795