Portal de Periódicos da CAPES

Mining for JAK–STAT mutations in cancer

2008; Elsevier BV; Volume: 33; Issue: 3 Linguagem: Inglês

10.1016/j.tibs.2007.12.002

1362-4326

Stefan N. Constantinescu, Michael Girardot, C. Pecquet,

Chronic Myeloid Leukemia Treatments

The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway mediates signaling by cytokines, which control survival, proliferation and differentiation of several cell types. Constitutive JAK activation leads to persistent activation of STAT transcription factors, and several cancers exhibit constitutive STAT activation, in the absence of JAK or STAT activating mutations. Recently, a unique somatic mutation in JAK2 was identified in a majority of patients with myeloproliferative neoplasms. This mutation, encoding a V617F substitution, promotes JAK2 catalytic activation and cytokine-independent signaling. JAK2 and JAK3 mutations have also been identified in a minority of polycythemia vera and acute megakaryoblastic leukemia patients, and it is predicted that further JAK–STAT mutations will be identified in different cancers. Recent discoveries also suggest that mutated JAK proteins will be potent targets for anti-cancer therapy. The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway mediates signaling by cytokines, which control survival, proliferation and differentiation of several cell types. Constitutive JAK activation leads to persistent activation of STAT transcription factors, and several cancers exhibit constitutive STAT activation, in the absence of JAK or STAT activating mutations. Recently, a unique somatic mutation in JAK2 was identified in a majority of patients with myeloproliferative neoplasms. This mutation, encoding a V617F substitution, promotes JAK2 catalytic activation and cytokine-independent signaling. JAK2 and JAK3 mutations have also been identified in a minority of polycythemia vera and acute megakaryoblastic leukemia patients, and it is predicted that further JAK–STAT mutations will be identified in different cancers. Recent discoveries also suggest that mutated JAK proteins will be potent targets for anti-cancer therapy. lethally irradiated mice die within a few weeks owing to severe failure of the hematopoietic system. Transplantation of bone marrow HSCs enables survival of these mice because the hematopoietic system is reconstituted with blood cells derived from the donor HSCs. Before transplantation, the bone marrow HSCs can be transduced with retroviruses encoding signaling proteins (e.g. JAK2 or JAK2 V617F) to determine the effect in vivo of these signaling proteins on blood formation. a number of cell types, especially blood precursors, depend on cytokines for survival, proliferation and differentiation. Several hematopoietic cell lines (e.g. BaF3 cells) have been established that proliferate and survive only in the presence of a particular cytokine. The expression of different cytokine receptors can promote growth dependence through the cognate cytokines. Cytokine-dependent cells do not induce tumors in immunocompromised mice. when cytokine-dependent cell lines acquire the ability to survive and proliferate in the absence of the appropriate cytokine(s), their growth becomes autonomous, or cytokine independent. These autonomous cells are considered to be transformed because they induce tumors in immunocompromised mice. Cytokine independence can be obtained through the expression of constitutively active forms of receptors, JAKs, STATs or several other oncoproteins, in cytokine-dependent cell lines. a family of cell surface receptors that act by stimulating the activity of intracellular protein-tyrosine kinases belonging to the Janus family. generic name for a class of cytokines in which the first discovered members (type I IFNs) interfere with viral replication. According to the type of receptor through which they signal, IFNs belong to three classes. Type I IFNs include multiple subtypes of IFN-α and IFN-β, and induce an antiviral state and antiproliferative effects in a variety of cell lines and tumor cells. Type I IFNs require the activation of JAK1 (bound to IFNAR2) and Tyk2 (bound to IFNAR1) for signaling. Type II IFN is represented by IFN-γ, which signals through JAK1 and JAK2 and is important for the immune response and immunosurveillance against cancer. initially denoted Just Another Kinase, JAKs were named after the Roman God Janus, the gatekeeper of heaven, who was described as having two faces. JAKs possess two tyrosine kinase domains, one that is catalytically active at the C-terminus, and another, denoted the pseudokinase domain, that is catalytically inactive. The pseudokinase domain performs a structural role and is predicted to prevent basal activity of the kinase domain. Based on conserved regions in the primary structure of the four mammalian JAKs, seven JAK-homology (JH) domains have been identified. From the C- to the N-terminus, the seven JH domains are: JH1, the kinase domain; JH2, the pseudokinase domain; JH3 to JH5; which contain an SH2-like domain; and JH6 to JH7, the FERM domain (a region homologous to band four point one of erythrocytes, ezrin, moezin, radixin). The FERM domain is required for the interaction with cytokine receptors. a signaling pathway in which STAT transcription factors are activated as a result of phosphorylation by members of the JAK family of protein kinases. renamed recently as myeloproliferative neoplasms, MPDs are a group of malignant hematological diseases which affect hematopoietic stem cells, leading to enhanced proliferation and formation of myeloid cells (erythrocytes, platelets and granulocytes). PV, ET and IMF are prototypes of these diseases, in which enhanced formation of erythrocytes, platelets and sometimes granulocytes results from cytokine independence and cytokine hypersensitivity in myeloid precursors. These diseases can progress to acute myeloid leukemia. a family of transcription factors containing seven members (STAT1, -2, -3, -4, -5A, -5B and -6) that have an SH2 domain, a DNA-binding domain and a transactivation domain. STATs are activated by phosphorylation of a tyrosine residue located in the C-terminus transactivation domain. STAT phosphorylation promotes dimerization and translocation from the cytoplasm to the nucleus. a family of transcription factors activated by TGF-β receptors. There are three classes of SMADs: (i) receptor-regulated SMADs (R-SMAD); (ii) the coSMAD SMAD4; and (iii) inhibitory SMADs (I-SMADs), SMAD6 and SMAD7. variegation denotes the occurrence within a tissue of sectors or regions with differing phenotypes. This phenotypic variegation results from the random alterations of chromatin marks that could activate or inhibit the expression of the gene responsible for a particular phenotype.