Cotargeting the JAK/STAT signaling pathway and histone deacetylase by ruxolitinib and vorinostat elicits synergistic effects against myeloproliferative neoplasms

2019 ◽  
Vol 38 (3) ◽  
pp. 610-620
Author(s):  
Xing Hao ◽  
Wen Xing ◽  
Jiajia Yuan ◽  
Yingshao Wang ◽  
Jiaojiao Bai ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Histone Deacetylase ◽  
Synergistic Effects ◽  
Myeloproliferative Neoplasms ◽  
Stat Signaling

scholarly journals Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Vladan P. Čokić ◽  
Olivera Mitrović-Ajtić ◽  
Bojana B. Beleslin-Čokić ◽  
Dragana Marković ◽  
Marijana Buač ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Myeloproliferative Neoplasms ◽  
Laboratory Data ◽  
Primary Myelofibrosis ◽  
Allele Burden ◽  
Protein Levels ◽  
Cytokine Levels ◽  
Stat Signaling ◽  
Marrow Stroma ◽  
V617f Mutation

The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34+cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) andJAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced byJAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34+cells of MPNs:CCND3andIL23Aregardless ofJAK2V617F allele burden;CSF3R, IL6ST, andSTAT1/2in ET and PV withJAK2V617F mutation; andAKT2, IFNGR2, PIM1, PTPN11, andSTAT3only in PV.STAT5Agene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent onJAK2V617F mutation presence in ET and PMF patients. Therefore, theJAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

scholarly journals Myeloproliferative neoplasms and the JAK/STAT signaling pathway: an overview

2015 ◽  
Vol 37 (5) ◽  
pp. 348-353 ◽  
Author(s):  
Renata Mendes de Freitas ◽  
Carlos Magno da Costa Maranduba
Keyword(s):  
Signaling Pathway ◽  
Myeloproliferative Neoplasms ◽  
Stat Signaling

scholarly journals Immune Dysregulation and Infectious Complications in MPN Patients Treated With JAK Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniele Cattaneo ◽  
Alessandra Iurlo
Keyword(s):  
Signaling Pathway ◽  
Current Knowledge ◽  
Myeloproliferative Neoplasms ◽  
Infectious Complications ◽  
Janus Kinase ◽  
Dramatic Improvement ◽  
Loss Of Function ◽  
Jak Inhibitors ◽  
Increased Risk ◽  
Stat Signaling

BCR-ABL1-negative myeloproliferative neoplasms are burdened by a reduced life expectancy mostly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. In these clonal myeloid malignancies, JAK2V617F is the main driver mutation, leading to an aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Therefore, its inhibition represents an attractive therapeutic strategy for these disorders. Several JAK inhibitors have entered clinical trials, including ruxolitinib, the first JAK1/2 inhibitor to become commercially available for the treatment of myelofibrosis and polycythemia vera. Due to interference with the JAK-STAT pathway, JAK inhibitors affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells. Therefore, even though the clinical use of these drugs in MPN patients has led to a dramatic improvement of symptoms control, organ involvement, and quality of life, JAK inhibitors–related loss of function in JAK-STAT signaling pathway can be a cause of different adverse events, including those related to a condition of immune suppression or deficiency. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors’ effects on immune cells as well as their clinical consequences, particularly with regards to infectious complications.

scholarly journals Glucocorticoids potentiate IL-6-induced SP-B expression in H441 cells by enhancing the JAK-STAT signaling pathway

2010 ◽  
Vol 299 (4) ◽  
pp. L578-L584 ◽  
Author(s):  
Andreas Ladenburger ◽  
Matthias Seehase ◽  
Boris W. Kramer ◽  
Wolfgang Thomas ◽  
Johannes Wirbelauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
Synergistic Effects ◽  
Regulation System ◽  
Mrna Levels ◽  
Α Subunit ◽  
Steroid Administration ◽  
Stat3 Phosphorylation ◽  
Antenatal Steroid ◽  
Stat Signaling

The respiratory distress syndrome (RDS) contributes to perinatal morbidity and mortality associated with preterm birth. Surfactant protein B (SP-B) is decreased in RDS. Both maternal antenatal steroid administration and chorioamnionitis reduce the incidence and severity of RDS. An important mediator in chorioamnionitis is IL-6 using the JAK-STAT signaling pathway for signal transduction. We hypothesized that the steroids, betamethasone (BTM) and dexamethasone (DXM), and IL-6 had synergistic effects on SP-B gene expression and STAT3 phosphorylation in H441 cells. DXM and BTM increased SP-B mRNA levels by 16.5 (13.3)-fold and IL-6 alone by 2.3-fold. After 48-h exposure of cells to DXM or BTM, IL-6 caused a significantly greater increase in SP-B mRNA levels (28.1-fold) than IL-6 or glucocorticoids alone. Whereas IL-6 stimulated tyrosine phosphorylation of STAT3 in a time- and dose-dependent way, DXM and BTM had no effect on STAT3 phosphorylation. Both DXM and BTM could potentiate IL-6-induced phosphorylation of STAT3. The synergism of glucocorticoids and IL-6 on SP-B gene expression and the effect of glucocorticoids on IL-6-induced STAT3 phosphorylation could be blocked by a JAK inhibitor. Expression level analysis showed that glucocorticoids increased the expression of the IL-6-binding α-subunit receptor (IL-6R) on mRNA and protein level. Our findings could represent an example of a pulmonary regulation system in which one role of glucocorticoids is to increase the effect of a cytokine by upregulation of its receptor. The described in vitro interaction of IL-6 and glucocorticoids could help explain the clinical observation that prenatal inflammation in preterm babies with antenatal steroid administration can attenuate severity of RDS.

Targeting the JAK/STAT Signaling Pathway for Breast Cancer.

2020 ◽  
Vol 28 ◽  
Author(s):  
Fei Shao ◽  
Xiaonan Pang ◽  
Gyeong Hun Baeg
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Signaling Pathway ◽  
Signal Transduction Pathway ◽  
Breast Cancer Treatment ◽  
Review Article ◽  
Transduction Pathway ◽  
Inhibitory Effects ◽  
Stat Proteins ◽  
Stat Signaling

Abstract:: Breast cancer is the most common malignant tumor in women worldwide. Traditional ways of treatment, includ-ing radiotherapy and endocrine therapy, for breast cancer have inevitable side effects. In recent decades, targeted therapies for breast cancer have rapidly advanced and shown a promising future. The JAK/STAT signaling pathway has been shown to play important roles in tumorigenesis, maintenance and metastasis of breast cancer. Hence, many small molecule inhibi-tors of JAK and STAT proteins have been developed. These inhibitors exhibit potent inhibitory effects on breast cancer in both cellular and animal models, and even some of them have already been in clinical trials. This review article discussed the JAK/STAT signal transduction pathway in the pathogenesis of breast cancer, and the potential for the application of JAK/STAT inhibitors in breast cancer treatment.

scholarly journals ChIP-seq Profiling Identifies Histone Deacetylase 2 Targeting Genes Involved in Immune and Inflammatory Regulation Induced by Calcitonin Gene-Related Peptide in Microglial Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Xingjing Guo ◽  
Dan Chen ◽  
Shuhong An ◽  
Zhaojin Wang
Keyword(s):  
Signaling Pathway ◽  
Histone Deacetylase ◽  
Calcitonin Gene Related Peptide ◽  
Epigenetic Mechanism ◽  
Microglial Cells ◽  
Transcriptional Level ◽  
Gene Promoters ◽  
Histone Deacetylase 2 ◽  
Related Peptide ◽  
Calcitonin Gene

Calcitonin gene-related peptide (CGRP) is a mediator of microglial activation at the transcriptional level. The involvement of the epigenetic mechanism in this process is largely undefined. Histone deacetylase (HDAC)1/2 are considered important epigenetic regulators of gene expression in activated microglia. In this study, we examined the effect of CGRP on HDAC2-mediated gene transcription in microglial cells through the chromatin immunoprecipitation sequencing (ChIP-seq) method. Immunofluorescence analysis showed that mouse microglial cells (BV2) expressed CGRP receptor components. Treatment of microglia with CGRP increased HDAC2 protein expression. ChIP-seq data indicated that CGRP remarkably altered promoter enrichments of HDAC2 in microglial cells. We identified 1271 gene promoters, whose HDAC2 enrichments are significantly altered in microglia after CGRP treatment, including 1181 upregulating genes and 90 downregulating genes. Bioinformatics analyses showed that HDAC2-enriched genes were mainly associated with immune- and inflammation-related pathways, such as nitric oxide synthase (NOS) biosynthetic process, retinoic acid-inducible gene- (RIG-) like receptor signaling pathway, and nuclear factor kappa B (NF-κB) signaling pathway. The expression of these key pathways (NOS, RIG-I, and NF-κB) were further verified by Western blot. Taken together, our findings suggest that genes with differential HDAC2 enrichments induced by CGRP function in diverse cellular pathways and many are involved in immune and inflammatory responses.

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