The Possible Role of the JAK/STAT Pathway in Lymphocytes at the Fetomaternal Interface

2005 ◽  
pp. 26-35 ◽  
Author(s):  
Tobias G. Poehlmann ◽  
Susann Busch ◽  
Bianka Mussil ◽  
Harald Winzer ◽  
Judith Weinert ◽  
...  
Keyword(s):  
Stat Pathway

Role of JAK-STAT pathway in pulmonary fibrosis

Pneumologie ◽  
2013 ◽  
Vol 67 (05) ◽  
Author(s):  
J Eschenbrenner ◽  
W Janssen ◽  
B Kojonazarov ◽  
K Murmann ◽  
A Ghofrani ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Stat Pathway

scholarly journals CSF3R T618I, SETBP1 G870S, SRSF2 P95H, and ASXL1 Q780* tetramutation co-contribute to myeloblast transformation in a chronic neutrophilic leukemia

2021 ◽  
Author(s):  
Yi Qian ◽  
Yan Chen ◽  
Xiaoming Li
Keyword(s):  
Alpha Interferon ◽  
Past Medical History ◽  
Variant Allele Frequency ◽  
Significant Past Medical History ◽  
Chronic Neutrophilic Leukemia ◽  
Hypercellular Marrow ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Stat Pathway

AbstractChronic neutrophilic leukemia (CNL) is a rare but serious myeloid malignancy. In a review of reported cases for WHO-defined CNL, CSF3R mutation is found in about 90% cases and confirmed as the molecular basis of CNL. Concurrent mutations are observed in CSF3R-mutated CNL patients, including ASXL1, SETBP1, SRSF2, JAK2, CALR, TET2, NRAS, U2AF1, and CBL. Both ASXL1 and SETBP1 mutations in CNL have been associated with a poor prognosis, whereas, SRSF2 mutation was undetermined. Our patient was a 77-year-old man and had no significant past medical history and symptoms with leukocytosis. Bone marrow (BM) aspirate and biopsy revealed a markedly hypercellular marrow with prominent left-shifted granulopoiesis. Next-generation sequencing (NGS) of DNA from the BM aspirate of a panel of 28 genes, known to be pathogenic in MDS/MPN, detected mutations in CSF3R, SETBP1, and SRSF2, and a diagnosis of CNL was made. The patient did not use a JAK-STAT pathway inhibitor (ruxolitinib) but started on hydroxyurea and alpha-interferon and developed pruritus after 4 months of diagnosis and nasal hemorrhage 1 month later. Then, the patient was diagnosed with CNL with AML transformation and developed intracranial hemorrhage and died. We repeated NGS and found that three additional mutations were detected: ASXL1, PRKDC, MYOM2; variant allele frequency (VAF) of the prior mutations in CSF3R, SETBP1, and SRSF2 increased. The concurrence of CSF3RT618I, ASXL1, SETBP1, and SRSF2 mutation may be a mutationally detrimental combination and contribute to disease progression and AML transformation, as well as the nonspecific treatment of hydroxyurea and alpha-interferon, but the significance and role of PRKDC and MYOM2 mutations were not undetermined.

scholarly journals Are STATS Arginine-methylated?

2005 ◽  
Vol 280 (23) ◽  
pp. 21700-21705 ◽  
Author(s):  
Waraporn Komyod ◽  
Uta-Maria Bauer ◽  
Peter C. Heinrich ◽  
Serge Haan ◽  
Iris Behrmann
Keyword(s):  
Arginine Methylation ◽  
Signaling Cascades ◽  
Post Translational Modification ◽  
Protein Arginine Methyltransferases ◽  
Stat Proteins ◽  
Fibrosarcoma Cells ◽  
Catalytically Active ◽  
Interferon Resistance ◽  
Stat Pathway

Transcription factors of the STAT (signal transducer and activator of transcription) family are important in signal transduction of cytokines. They are subject to post-translational modification by phosphorylation on tyrosine and serine residues. Recent evidence suggested that STATs are methylated on a conserved arginine residue within the N-terminal region. STAT arginine methylation has been described to be important for STAT function and loss of arginine methylation was discussed to be involved in interferon resistance of cancer cells. Here we provide several independent lines of evidence indicating that the issue of arginine methylation of STATs has to be reassessed. First, we show that treatment of melanoma and fibrosarcoma cells with inhibitors used to suppress methylation (N-methyl-2-deoxyadenosine, adenosine, dl-homocysteine) had profound and rapid effects on phosphorylation of STAT1 and STAT3 but also on p38 and Erk signaling cascades which are known to cross-talk with the Jak/STAT pathway. Second, we show that anti-methylarginine antibodies did not precipitate specifically STAT1 or STAT3. Third, we show that mutation of Arg31 to Lys led to destabilization of STAT1 and STAT3, implicating an important structural role of Arg31. Finally, purified catalytically active protein arginine methyltransferases (PRMT1, -2, -3, -4, and -6) did not methylate STAT proteins, and cotransfection with PRMT1 did not affect STAT1-controlled reporter gene activity. Taken together, our data suggest the absence of arginine methylation of STAT1 and STAT3.

Abstract IA41: Role of JAK-STAT pathway activation in MPN pathogenesis and therapeutic response.

2015 ◽  
Author(s):  
Sara Meyer ◽  
Maria Kleppe ◽  
Neha Bhagwat ◽  
Priya Koppikar ◽  
Minsuk Kwak ◽  
...  
Keyword(s):  
Therapeutic Response ◽  
Pathway Activation ◽  
Stat Pathway

scholarly journals Receptors for interleukin-3 (IL-3) and growth hormone mediate an IL-6- type transcriptional induction in the presence of JAK2 or STAT3

Blood ◽  
1995 ◽  
Vol 86 (5) ◽  
pp. 1671-1679 ◽  
Author(s):  
Y Wang ◽  
KK Morella ◽  
J Ripperger ◽  
CF Lai ◽  
DP Gearing ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Expression Vectors ◽  
Protein Activation ◽  
Stat Proteins ◽  
Interleukin 3 ◽  
Dose Dependent ◽  
Transcriptional Induction ◽  
Stimulation Of ◽  
Stat Pathway

To determine the specificity of signal transducer and activator of transcription (STAT) protein activation by box 3 motif-deficient hematopoietin receptors, expression vectors encoding the receptors for growth hormone, interleukin-3 (IL-3), and IL-4 were transiently transfected into COS-1 cells, together with expression vectors for Janus kinases (JAKs) and STAT proteins. Each receptor mediated a dose- dependent activation of STAT1 and STAT3, and for IL-3R and GHR this process was enhanced by JAK2. The data suggest that a box 3 motif in the cytoplasmic domain of the signal-transducing receptor to the JAK/STAT pathway. Transfection of the receptors, in combination with STAT3, into HepG2 cells reconstituted a cytokine-dependent stimulation of gene transcription through IL-6 response elements, providing evidence for a functional role of STAT3 in controlling gene expression.

scholarly journals Targeting Signal Transducer and Activator of Transcription Signaling Pathway in Leukemias

2009 ◽  
Vol 27 (26) ◽  
pp. 4422-4432 ◽  
Author(s):  
Mustafa Benekli ◽  
Heinz Baumann ◽  
Meir Wetzler
Keyword(s):  
Potential Role ◽  
Cellular Transformation ◽  
Therapeutic Strategies ◽  
Signal Transducer ◽  
Stat Proteins ◽  
Constitutive Activation ◽  
Targeting Signal ◽  
Novel Therapeutic Strategies ◽  
Stat Pathway

Signal transducer and activator of transcription (STAT) proteins comprise a seven-member family of latent cytoplasmic transcription factors that are activated through tyrosine phosphorylation by a variety of cytokines and growth factors. Aberrant activation of STATs accompanies malignant cellular transformation with resultant leukemogenesis. Constitutive activation of STATs has been demonstrated in various leukemias. A better understanding of the mechanisms of dysregulation of the STAT pathway and understanding of the cause and effect relationship in leukemogenesis may serve as a basis for designing novel therapeutic strategies directed against STATs. Mechanisms of STAT activation, the potential role of STAT signaling in leukemogenesis, and recent advances in drug discovery targeting the STAT pathway are the focus of this review.

scholarly journals An essential role of the JAK-STAT pathway in ischemic preconditioning

2001 ◽  
Vol 98 (16) ◽  
pp. 9050-9055 ◽  
Author(s):  
Y.-T. Xuan ◽  
Y. Guo ◽  
H. Han ◽  
Y. Zhu ◽  
R. Bolli
Keyword(s):  
Ischemic Preconditioning ◽  
Essential Role ◽  
Stat Pathway

Inhibition Of JAK-STAT Pathway As a Therapeutic Option For Myelofibrosis Associated Pulmonary Hypertension

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1585-1585 ◽  
Author(s):  
Ali Tabarroki ◽  
Daniel Lindner ◽  
Valeria Visconte ◽  
Li Zhang ◽  
Edy Hasrouni ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Conflicts Of Interest ◽  
Systolic Pressure ◽  
Right Atrial ◽  
No Production ◽  
Stat Signaling ◽  
Echocardiographic Findings ◽  
Stat Pathway

Abstract Pulmonary hypertension (PH) is an under-recognized complication of myelofibrosis (MF) occurring in 30% of MF patients and associated with poor survival. Echocardiographic diagnostic findings include; elevated right ventricular systolic pressure (RVSP)>35 mmHg, right atrial (RA) enlargement and increased tricuspid regurgitation velocity (TRV) ≥2.5 m/sec. The pathophysiology of PH in MF has not been elucidated, although in idiopathic PH, the proliferation of pulmonary artery endothelial cells has been linked to activation of STAT3 pathway. Dysregulation of JAK-STAT pathway has been implicated in the pathogenesis of MF. Ruxolitinib, a JAK1/2 inhibitor, was approved for management of splenomegaly and cytokine-mediated symptoms in MF. Furthermore, no specific therapy in the management of MF-associated PH has been established. Given the association between MF and PH and the possible pathophysiologic link mediated by JAK signaling, we prospectively followed 19 patients with MF-associated PH and compared their echocardiographic findings and PH relevant serum biomarker levels (nitric oxide [NO], NT-pro brain natriuretic peptide [NT-proBNP], von Willebrand antigen (vWB), ristocetin co-factor (RCA), and uric acid (UA) pre- and post-ruxolitinib therapy. All categorical data were summarized for frequency, counts and percentages, and the comparison between two groups was performed by two-sample Wilcoxon signed rank test. Among 19 patients (pts), 9 had PMF, 5 post-ET MF, 4 post-PV MF and one CMML-1. In this cohort, 11 were females and 8 were males. The median age of the cohort was 68 years (range, 50-81 years). Fifteen pts were JAK2 V617F positive and 4 were wild-type, 8 were intermediate-1, 4 intermediate-2 and 6 high risk per Dynamic International Prognostic Scoring System-Plus risk grouping. The mean ruxolitinib dose was 10 mg BID (range: 5 mg QOD-20 mg BID]. Median duration of disease was 32 mos (6-164 mos), ruxolitinib duration of treatment was 10 mos (4 -17 mos) and follow-up was 11 mos (6-22 mos). Prior to the initiation of ruxolitinib treatment, NT-pro BNP levels, were measured and found to be elevated in 90% (17/19) of pts. In addition, UA, vWB, and RCA levels were all elevated in 47% (9/19), 24% (4/17), and 12% (2/17) of pts respectively. The strongest correlation among serum biomarkers was between plasma vWB and RCA levels (r2=-0.89, P=<.001). The biomarker most closely associated with elevated NT-pro BNP was UA both in the pre- (r2=-0.53, P=.065) and post-treatment (r2=-0.64, P=.019) settings. Echocardiographic findings by TTE pre- and post ruxolitinib therapy were available for 12 pts (63%). All 12 had documented PH with a mean RVSP of 47.5 mm Hg (42-68) [normal pressure ≤30 mmHg]. Echocardiographic evidence correlated with RCA (r2=-0.64, P= .045) and plasma NT-pro BNP levels (r2=-0.8, P=.013). Ruxolitinib resulted in reductions in NT-pro BNP level (88%) (p=.013), plasma UA levels in (71%), vWB (71%), and RCA (71%) (P=.045). Nitric oxide, a primary regulator of vascular endothelial function is reduced in MF patients with PH compared to normal individuals (median NO, 36 vs 65 pM). Treatment with ruxolitinib resulted in marked increase in NO levels compared to baseline (68 pM vs 36 pM; P=0.04) while no changes in NO levels were observed after treatment with hydroxyurea and lenalidomide (N=10). Treatment with ruxolitinib also resulted in reduction of key cytokines (TNF-α, IL-4, IL-10) that inhibit NO production and induction of cytokines (IFN-γ) that lead to increase in NO synthesis supporting the role of cytokines in PH pathogenesis in MF. Murine studies further supported the role of ruxolitinib in induction of NO levels. Eight normal CD-1 mice were treated with ruxolitinib (50 mg/kg p.o. daily for 5 days for three consecutive cycles with 14 day intervals between each cycle). After the first cycle, NO levels were significantly higher compared to baseline followed by significant increase compared to baseline at cycle 3 (P=.04). In addition, PH mice (Caveoline-1 mice) have been bred and undergoing treatment with ruxolitinib to assess changes in NO levels and its impact in improving of PH. In conclusion, aberrant JAK-STAT signaling in MF mediates PH by dysregulation of NO and cytokines levels which can be restored by therapy with JAK inhibitors. This suggests that inhibition of the JAK-STAT signaling pathway is a novel and viable target for the management of patients with MF-associated PH. Disclosures: No relevant conflicts of interest to declare.

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