Genetic factors in chronic inflammation: Single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn's disease in a New Zealand population

Ferguson, Lynnette R.; Han, Dug Yeo; Fraser, Alan G.; Hüebner, Claudia; Lam, Wen Jiun; Morgan, Angharad R.; Duan, He; Karunasinghe, Nishi

doi:10.1016/j.mrfmmm.2010.01.017

Cited by 107 publications

(107 citation statements)

References 26 publications

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“…30 Enhanced susceptibility to DNA damage was estimated by comet assays in peripheral blood leukocytes of healthy 46/1 carriers indicating genomic instability affecting not exclusively the JAK2 locus. 31 The "fertile ground hypothesis" suggests that 46/1 haplotype carriers may have subtle differences in JAK2 function compared to 46/1 non-carriers, which increase the predisposition to clonal myeloproliferation. Indeed, healthy 46/1 haplotype carriers were reported to have reduced granulocytemacrophage colony formation.…”

Section: Discussionmentioning

confidence: 99%

“…The impairment of JAK2 function was suggested to affect interleukin-23 signaling and the differentiation of pro-inflammatory T cells (Th17) in inflammatory bowel disease. [31][32][33][34] On the other hand, several lines of evidence suggest that there is defective GM-CSF signaling in inflammatory bowel disease: decreased GM-CSF secretion, 35 neutralizing autoantibodies against GM-CSF, 36 and defective GM-CSF receptor expression and function 37 were described as characteristic features of inflammatory bowel disease. Compromised GM-CSF signaling resulting in functional abnormality of neutrophils and macrophages facilitates the invasion of the epithelial barrier by intestinal bacteria.…”

Section: Discussionmentioning

confidence: 99%

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The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

et al. 2011

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The online version of this article has a Supplementary Appendix. BackgroundPrognostic risk stratification according to acquired or inherited genetic alterations has received increasing attention in acute myeloid leukemia in recent years. A germline Janus kinase 2 haplotype designated as the 46/1 haplotype has been reported to be associated with an inherited predisposition to myeloproliferative neoplasms, and also to acute myeloid leukemia with normal karyotype. The aim of this study was to assess the prognostic impact of the 46/1 haplotype on disease characteristics and treatment outcome in acute myeloid leukemia. Design and MethodsJanus kinase 2 rs12343867 single nucleotide polymorphism tagging the 46/1 haplotype was genotyped by LightCycler technology applying melting curve analysis with the hybridization probe detection format in 176 patients with acute myeloid leukemia under 60 years diagnosed consecutively and treated with curative intent. ResultsThe morphological subtype of acute myeloid leukemia with maturation was less frequent among 46/1 carriers than among non-carriers (5.6% versus 17.2%, P=0.018, cytogenetically normal subgroup: 4.3% versus 20.6%, P=0.031), while the morphological distribution shifted towards the myelomonocytoid form in 46/1 haplotype carriers (28.1% versus 14.9%, P=0.044, cytogenetically normal subgroup: 34.0% versus 11.8%, P=0.035). In cytogenetically normal cases of acute myeloid leukemia, the 46/1 carriers had a considerably lower remission rate (78.7% versus 94.1%, P=0.064) and more deaths in remission or in aplasia caused by infections (46.8% versus 23.5%, P=0.038), resulting in the 46/1 carriers having shorter disease-free survival and overall survival compared to the 46/1 non-carriers. In multivariate analysis, the 46/1 haplotype was an independent adverse prognostic factor for disease-free survival (P=0.024) and overall survival (P=0.024) in patients with a normal karyotype. Janus kinase 2 46/1 haplotype had no impact on prognosis in the subgroup with abnormal karyotype. ConclusionsJanus kinase 2 46/1 haplotype influences morphological distribution, increasing the predisposition towards an acute myelomonocytoid form. It may be a novel, independent unfavorable risk factor in acute myeloid leukemia with a normal karyotype.Key words: acute myeloid leukemia, prognosis, Janus kinase 2, 46/1 haplotype. Haematologica 2011;96(11):1613-1618. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Nahajevszky S, Andrikovics H, Batai A, Adam E, BorsThe prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

et al. 2011

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“…The '46/1' haplotype is also associated with chronic inflammation, notably inflammatory bowel disease (Ferguson et al, 2010). Interestingly, although most evident in primary myelofibrosis, signs of chronic inflammation, such as increased production of inflammatory cytokines, interleukin (IL)-6 and vascular endothelial growth factor, are also observed in PV and in ET (Wickenhauser et al, 1999;Musolino et al, 2002;Panteli et al, 2005;Le Bousse-Kerdile´s and Martyre´, 1999).…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

et al. 2010

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The V617F activating mutation of janus kinase 2 (JAK2), a kinase essential for cytokine signalling, characterizes Polycythemia vera (PV), one of the myeloproliferative neoplasms (MPN). However, not all MPNs carry mutations of JAK2, and in JAK2-mutated patients, expression of JAK2V617F does not always result in clone expansion. In the present study, we provide evidence that inflammation-linked cytokines are required for the growth of JAK2V617F-mutated erythroid progenitors. In a first series of experiments, we searched for cytokines overexpressed in PV using cytokine antibody (Ab) arrays, and enzyme-linked immunosorbent assays for analyses of serum and bone marrow (BM) plasma, and quantitative reverse transcription-PCRs for analyses of cells purified from PV patients and controls. We found that PV patients over-expressed anti-inflammatory hepatocyte growth factor (HGF) and interleukin-11 (IL-11), BM mesenchymal stromal cells (BMMSCs) and erythroblasts being the main producers. In a second series of experiments, autocrine/paracrine cytokine stimulation of erythroblasts was blocked using neutralizing Abs specific for IL-11 or c-MET, the HGF receptor. The growth of JAK2V617F-mutated HEL cells and PV erythroblasts was inhibited, indicating that JAK2-mutated cells depend on HGF and IL-11 for their growth. Additional experiments showed that transient expression of JAK2V617F in BaF-3/erythropoietin receptor cells, and invalidation of JAK2V617F in HEL cells using anti-JAK2 small interfering RNA, did not affect HGF and IL-11 expression. Thus, anti-inflammatory HGF and IL-11 are upregulated in PV and their overproduction is not a consequence of JAK2V617F. As both cytokines contribute to the proliferation of PV erythroblasts, blocking the c-MET/ HGF/IL-11 pathways could be of interest as an additional therapeutic option in PV.

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“…The RT-PCR procedure was completed using the PimerDesign®SNPsig Real-Time PCR mutation detection/allelic discrimination Kit (PrimerDesign Ltd.; Southampton, UK) in accordance with the manufacturer's protocol (23). The rs11209026 (G>A, R381Q) of the IL23R gene, rs10758669 (A>C) of the JAK2 gene, and rs3816769 (T>C), rs2293152 (G>C), rs744166 (C>T), rs957970 (C>T), and rs8074524 (C>T) of the STAT3 gene were examined in the obtained genomic DNA (16,17,(19)(20)(21). The prepared 20 μL PCR solution contained 10 μL PimerDesign®2xPrecision MasterMix, 1 μL Primer/probe mix, 4 μL water not containing ribonuclease and deoxyribonuclease, and 5 μL genomic DNA for each reaction.…”

Section: Extraction Of Genomic Dna and Genotypingmentioning

confidence: 99%

“…It is thought that the IL23/IL23R signal pathway may play a central role in the pathogenesis of IBD. Though there are studies showing that IL23R, JAK2, and STAT3 cause susceptibility to UC and CD in different ethnic groups, the results are not consistent (6,13,(15)(16)(17)(18)(19)(20)(21). The reason for this discrepancy may be that IBD in different ethnic communities may appear through different predominant mechanisms.…”

Section: Introductionmentioning

confidence: 98%

Investigation of IL23R, JAK2, and STAT3 gene polymorphisms and gene–gene interactions in Crohn’s disease and ulcerative colitis in a Turkish population

Can¹,

Tezel²,

Gürkan³

et al. 2016

Turk J Gastroenterol

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Genetic factors in chronic inflammation: Single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn's disease in a New Zealand population

Cited by 107 publications

References 26 publications

The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia

Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

Investigation of IL23R, JAK2, and STAT3 gene polymorphisms and gene–gene interactions in Crohn’s disease and ulcerative colitis in a Turkish population

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