scholarly journals Pseudocirrhosis in Chronic Budd Chiari Syndrome With Janus Tyrosine Kinase 2 (JAK2) Mutation

Cureus ◽  
2020 ◽  
Author(s):  
Seetha Lakshmanan ◽  
Dhanya Baskaran ◽  
Yashvin Onkarappa Mangala ◽  
Nabil Toubia
Keyword(s):  
Tyrosine Kinase ◽  
Budd Chiari Syndrome ◽  
Jak2 Mutation ◽  
Tyrosine Kinase 2 ◽  
Chiari Syndrome ◽  
Janus Tyrosine Kinase 2

Myeloproliferative Disease in the Pathogenesis and Survival of Budd-Chiari Syndrome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1480-1480
Author(s):  
Jasper H. Smalberg ◽  
Sarwa D. Murad ◽  
Eric Braakman ◽  
Peter Valk ◽  
Mies C. Kappers-Klunne ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Survival Rates ◽  
Vena Cava ◽  
Aetiological Factor ◽  
Budd Chiari Syndrome ◽  
Jak2 Mutation ◽  
Who Criteria ◽  
Significant Difference ◽  
Chiari Syndrome

Abstract Budd-Chiari syndrome (BCS) is a rare disorder caused by obstruction of the hepatic veins or the suprahepatic inferior vena cava. Myeloproliferative diseases (MPD) are the most important aetiological factor in BCS. The aim of this study was to evaluate multifactorial aetiology in BCS patients with MPD, to assess potential added value of the recently discovered JAK2 mutation in the diagnostics of MPD in BCS, and to determine the survival of MPD patients in BCS. All patients referred to our university hospital with primary, non-malignant BCS between January 1980 and January 2006 were included in this study (n=40). Median age was 28.4 years (18.4–53.3), 26 patients (65%) were female and in nine patients (23%) additional portal vein thrombosis (PVT) was present. Overall mean follow-up was 7.1 ± 6.9 years. Only two patients were lost to follow-up, of which one MPD patient. In addition to standard MPD work-up according to WHO criteria, JAK2 mutation analysis was performed in 17 patients. MPD was present in 33% of the patients: Polycythemia Vera (n=6), Essential Thrombocythemia (ET) (n=6) and unclassifiable MPD (n=1). JAK2 mutation was identified in seven out of the 17 tested BCS patients (41%). In two patients suspect for ET, but who failed to meet WHO criteria, JAK2 mutation analysis led to the diagnosis of MPD. In 38% of patients with MPD additional pro-thrombotic factors were present. Survival rates in patients with MPD at 1, 5, and 10 years remained constant at 92% (95% CI, 78%–100%). Survival rates in patients without MPD at 1, 5, and 10 years were 89% (95% CI, 77%–100%), 64% (95% CI, 44%–85%) and 53% (95% CI, 28%–79%), respectively. There was no significant difference in survival between the two (P=0.18). Additional PVT was only present in patients without MPD in our population, which may account for the slightly lowered survival of these patients, since more extensive thrombosis in the splanchnic area is associated with poorer survival. In addition, three patients with and one patients without MPD underwent liver transplantation, which may have affected survival rate in favour of MPD patients. In conclusion, we report MPD in 33% of our BCS patients. In 38% of the patients with MPD, additional pro-thrombotic factors were present. These results enforce the necessity of extensive screening for additional pro-thrombotic conditions. Our study clearly confirms the importance of JAK2 mutation analysis in patients with BCS. Long term follow-up did not show a significant difference in survival between patients with and without MPD.

The JAK2V617F Mutation Is Present in the Liver Endothelial Cells of Patients with Budd-Chiari Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2795-2795
Author(s):  
Selcuk Sozer ◽  
Isabel M. Fiel ◽  
Thomas Schiano ◽  
Faye Feller ◽  
John Mascarenhas ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Liver Biopsy ◽  
Jak2v617f Mutation ◽  
Proliferative Potential ◽  
Wild Type ◽  
Budd Chiari Syndrome ◽  
Jak2 Mutation ◽  
Vein Thrombosis ◽  
Specific Pcr ◽  
Chiari Syndrome

Abstract Post-natal vasculogenesis has been reported to be derived from a hierarchy of circulating endothelial progenitor cells (EPC). Some of these EPC are of myeloid origin while others have a more robust proliferative potential and are solely of endothelial cell (EC) origin. A number of groups have hypothesized that EC dysfunction might contribute to the hypercoagulable state associated with polycythemia vera (PV) by orchestrating the recruitment of blood elements to sites of injury or by regulating vascular tone. The JAK2V617F mutation is present in >95% of patients with PV. In addition, some individuals with normal blood counts who develop splanchnic vein thrombosis, including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) have been reported to have JAK2V617F positive hematopoiesis (45% and 34%, respectively) indicating that this thrombotic tendency might precede the development of PV. We explored whether this activating mutation is present in EC in the vessels of patients with BCS. We tested this hypothesis by studying EC in venules of liver biopsy specimens of patients with BCS with (n=2) or without PV (n=1) and PVT (n=2) without PV using laser capture microdissection (LCM) followed by nested PCR or RT-PCR in order to determine if EC were JAK2V617F positive and were of hematopoietic or EC origin. EC from the hepatic venules of BCS and PVT patients were captured by LCM from hematoxylin and eosin stained sections of archival formalin-fixed paraffin-embedded liver biopsy tissue specimens. EC were identified by their fusiform nuclei and their location along the lining of the hepatic venules. Hepatocytes were identified by their morphology as having round centrally placed nuclei and abundant cytoplasm with a trabecular arrangement. At least 10 EC and 10 hepatocytes from each biopsy specimen were captured and DNA or RNA was extracted. The JAK2V617F mutation was detected using nested allele-specific PCR. The hepatocytes of each patient contained exclusively wild type JAK2 while the EC of the two BCS patients with PV were homozygous for the JAK2V617F. The EC of the other BCS patient and 2 PVT patients who did not have PV contained exclusively wild type JAK2. The EC identity of these cells in the PV patients was confirmed by the presence of the EC transcripts (VE-Cadherin and VEGF-R2) and the absence of hematopoietic cell transcripts (CD45 and CD14). These findings indicate that hepatic venule EC in BCS patients with PV are JAK2V617F positive. The presence of JAK2V617F in both endothelial cells and hematopoietic cells belonging to such patients suggests that PV originates in an adult hemangioblast like cell in such patients. Further studies are required to understand the consequence of JAK2 mutation in EC as related to their propensity to thrombosis in PV.

scholarly journals Tyrosyl Phosphorylated PAK1 Regulates Breast Cancer Cell Motility in Response to Prolactin through Filamin A

2013 ◽  
Vol 27 (3) ◽  
pp. 455-465 ◽  
Author(s):  
Alan Hammer ◽  
Leah Rider ◽  
Peter Oladimeji ◽  
Leslie Cook ◽  
Quanwen Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cell Motility ◽  
Small Gtpase ◽  
Actin Binding ◽  
Filamin A ◽  
T47d Cells ◽  
Tyrosine Kinase 2 ◽  
Janus Tyrosine Kinase 2

Abstract The p21-activated serine-threonine kinase (PAK1) is activated by small GTPase-dependent and -independent mechanisms and regulates cell motility. Both PAK1 and the hormone prolactin (PRL) have been implicated in breast cancer by numerous studies. We have previously shown that the PRL-activated tyrosine kinase JAK2 (Janus tyrosine kinase 2) phosphorylates PAK1 in vivo and identified tyrosines (Tyr) 153, 201, and 285 in the PAK1 molecule as sites of JAK2 tyrosyl phosphorylation. Here, we have used human breast cancer T47D cells stably overexpressing PAK1 wild type or PAK1 Y3F mutant in which Tyr(s) 153, 201, and 285 were mutated to phenylalanines to demonstrate that phosphorylation of these three tyrosines are required for maximal PRL-dependent ruffling. In addition, phosphorylation of these three tyrosines is required for increased migration of T47D cells in response to PRL as assessed by two independent motility assays. Finally, we show that PAK1 phosphorylates serine (Ser) 2152 of the actin-binding protein filamin A to a greater extent when PAK1 is tyrosyl phosphorylated by JAK2. Down-regulation of PAK1 or filamin A abolishes the effect of PRL on cell migration. Thus, our data presented here bring some insight into the mechanism of PRL-stimulated motility of breast cancer cells.

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