A New Polycythemia Syndrome: Congenital Polycythemia with High Erythropoietin and Propensity for Malignant Hypertension Due to Paraganglioma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4345-4345
Author(s):  
Yongli Guan ◽  
John K. Wu ◽  
Wasil Jastaniah ◽  
Larry G. Moss ◽  
Colleen Digman ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Germ Line ◽  
Hypoxia Inducible Factor ◽  
Malignant Hypertension ◽  
Compound Heterozygous ◽  
Molecular Defect ◽  
Erythroid Progenitors ◽  
Von Hippel Lindau ◽  
Normal Sensitivity ◽  
Endothelial Growth Factor

Abstract We report three patients, two females and one male, with congenital polycythemia and high erythropoietin. All were extensively investigated in childhood; no known polycythemic conditions were diagnosed nor were any tumors known to be associated with polycythemia uncovered. At the ages of 14, 16, and 32 years the patients developed malignant hypertension secondary to multiple paragangliomas. In addition, one of patients has also developed a malignant pancreatic carcinoid tumor that expressed somatostatin. After the surgical resection of paragangliomas, hypertension subsided, but polycythemia persisted in all three subjects. Comprehensive screening for germ-line mutations of von Hippel-Lindau (VHL) gene as well as genes known to be causing familial paragangliomas - catalytic succinate dehydrogenase subunits B (SDHB), and catalytic succinate dehydrogenase subunit D (SDHD), has not revealed any mutations. In one of these patients studied so far there was no abnormality of the any of the three hypoxia control associated proline hydroxylase genes expressions found. Unlike the erythroid progenitors of Chuvash Polycythemia, these patients had normal sensitivity of erythroid progenitors to erythropoietin. The search for somatic mutations of VHL, SDHB, and SDHD genes, as well as quantitative analysis of the expressions of hypoxia inducible factor 1 alpha subunit (HIF-1a), vascular endothelial growth factor (VEGF), VHL, SDHB, and SDHD mRNAs by real-time PCR is ongoing. In summary, we report a new polycythemic syndrome of congenital polycythemia with high erythropoietin and the normal sensitivity of erythroid progenitors to erythropoietin, which is not associated with VHL mutation. This is in contrast to our previous experience with about 200 patients, homozygous for Chuvash Polycythemia mutation or compound heterozygous for Chuvash Polycythemia R200W and other VHL mutations, who have not developed paraganglioma or any VHL syndrome tumors. This new polycythemic syndrome shares some clinical features with both von Hippel Lindau syndrome and with the Chuvash polycythemia. While its molecular defect is yet to be elucidated, it is a distinct clinical and genetic entity.

scholarly journals Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice

2005 ◽  
Vol 25 (8) ◽  
pp. 3163-3172 ◽  
Author(s):  
Erinn B. Rankin ◽  
Debra F. Higgins ◽  
Jacqueline A. Walisser ◽  
Randall S. Johnson ◽  
Christopher A. Bradfield ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Line ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Vascular Tumors ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Arylhydrocarbon Receptor ◽  
Vhl Disease ◽  
Endothelial Growth Factor

ABSTRACT Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

Neue und vielversprechende molekulare Therapieoptionen in verschiedenen Subtypen des Nierenzellkarzinoms

2017 ◽  
Vol 74 (4) ◽  
pp. 171-179 ◽  
Author(s):  
Niels J. Rupp ◽  
Axel Mischo ◽  
Holger Moch
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Monoklonale Antikörper ◽  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Zielgerichtete Therapien ◽  
Von Hippel Lindau ◽  
Genetische Heterogenität ◽  
Endothelial Growth Factor

Zusammenfassung. Nierenzellkarzinome bilden eine heterogene Gruppe von Karzinomen mit verschiedenen histologischen Subtypen. Die Mehrheit der Nierenzellkarzinome beim Erwachsenen sind klarzellige Nierenzellkarzinome (ccRCC), welche durch Alterationen im von Hippel-Lindau (VHL) Gen charakterisiert sind. Neue Erkenntnisse zeigen dabei die genetische Heterogenität dieser Entität und das Vorhandensein von mindestens drei zusätzlichen ccRCC Tumorsuppressorgenen auf dem Chromosom 3p. Aufgrund der Inaktivierung von VHL produzieren die Nierenzellkarzinomzellen den auf Hypoxia Inducible Factor (HIF) reagierenden Wachstumsfaktor vascular endothelial growth factor (VEGF). Die neuen systemischen Therapien, inklusive Tyrosinkinasehemmer, monoklonale Antikörper und mTOR-Inhibitoren zielen darauf ab, die Angiogenese zu inhibieren, indem sie die VEGF Wirkung inhibieren. In Nierenzellkarzinomen, die mit erblichen Tumorsyndromen assoziiert sein können bzw. dort initial beschrieben wurden, sind spezifische Genaberrationen identifiziert worden, z. B. in den Genen FLCN, TFE3, TFEB, MITF, FH, SDHB, SDHD und MET. Diese Arbeit soll eine Übersicht über die Fortschritte in der molekularen Therapie des metastasierten ccRCC geben und zusätzlich auf Genese, Prognose und potenzielle zielgerichtete Therapien weiterer morphologisch und molekular definierter Nierenzellkarzinome eingehen.

Erythrocytosis Caused by Mutations in the PHD2 and VHL Genes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3663-3663 ◽  
Author(s):  
Melanie J. Percy ◽  
Paul W. Furlow ◽  
Frank G.C. Jones ◽  
Terry R.J. Lappin ◽  
Frank S. Lee ◽  
...  
Keyword(s):  
Target Genes ◽  
Tertiary Structure ◽  
Oxygen Sensing ◽  
Protein A ◽  
Hypoxia Inducible Factor ◽  
Feedback Mechanism ◽  
Compound Heterozygous ◽  
Von Hippel Lindau ◽  
Negative Feedback Mechanism ◽  
Binding Groove

Abstract Human diseases have provided important insights into the function of fundamental physiological processes, and studying erythrocytosis has increased our understanding of the oxygen sensing pathway. In some cases this rare disorder arises specifically from dysregulation of the erythropoietin (Epo) axis. Epo gene transcription is under the control of a negative feedback mechanism involving the kidneys, which sense tissue hypoxia at the molecular level via the hypoxia inducible factor (HIF) transcription complex. Both subunits of the HIF complex, alpha and beta, are constitutively expressed but only the beta subunit is detectable in the presence of oxygen. Key prolines in the oxygen degradation domain of HIFalpha are hydroxylated by a family of prolyl hydroxylase enzymes, PHD1-3. Of these PHD2 has the most widespread tissue distribution. Upon hydroxylation of HIF, the von Hippel Lindau (VHL) protein, a component of an E3 ligase complex, promotes the ubiquitination of the alpha subunit. HIFalpha is then targeted to the proteasome and the transcription of HIF target genes is prevented. In hypoxia the activity of the PHD enzymes is low and the HIF complex assembles causing upregulation of genes such as Epo. Over the last ten years we have maintained a registry of individuals with erythrocytosis. To date 181 patients have been included with clinical details and consented DNA samples have been collected. There is a preponderance of males with ratio of 1.7 males to each female. The mean age of erythrocytosis individuals on the registry is 37 years. The majority of erythrocytosis patients have inappropriately normal (46%) or raised (26%) serum Epo levels as compared to PV, where the Epo level is often undetectable. Thus it can be inferred that dysregulation of the Epo axis via the oxygen sensing pathway would be a significant cause of erythrocytosis. Consequently, PHD2 and VHL have been investigated. We have now identified 2 different mutations, Pro317Arg and Arg371His, in PHD2. In the tertiary structure of PHD2, Pro317and Arg371 are close to essential iron binding residues and furthermore suggest the location of a HIF binding groove. The Arg200Trp VHL mutation, commonly described as the Chuvash mutation, has been detected in 8 Asian families and their large kindred. Two Western European individuals were found to be compound heterozygous for the Arg200Trp and either the novel Pro192Thr or Gly144Arg variants. Intriguingly 2 further individuals possess one wild type and one mutated allele, Arg200Trp or Leu188Val. Screening other genes of the oxygen sensing pathway has failed to reveal further defects in these individuals. In summary, defects in the oxygen sensing pathway are associated with the development of erythrocytosis. Mutations in VHL are more common than PHD2 and highlight the importance of these proteins in the maintenance of red cell homeostasis.

Expression of the Hypoxia-Inducible Factors In the AML and MDS: Is Not Associated with the Von Hippel-Lindau Gene

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5114-5114
Author(s):  
Hongyan Tong ◽  
Chen Mei ◽  
Kongfei Li ◽  
Jie Jin
Keyword(s):  
Conflicts Of Interest ◽  
Methylation Status ◽  
Tumor Biology ◽  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Coding Region ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Genes Encoding ◽  
Endothelial Growth Factor

Abstract Abstract 5114 The hypoxia-inducible factor (HIF) is a transcriptional factor with important roles in tumor biology, which activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. The VHL (von Hippel-Lindau) gene normally regulates ubiquitin mediated proteolysis of HIF-1a. VHL inactivation blocks HIF-1 proteolysis, resulting in increased HIF-1 expression. In the previous study, the expression of HIF-1a was detected in children ALL and NHL. To clarify the possible involvement of the HIF-1a and VHL gene in the development and progression of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), we analyzed the mutation and methylation of the VHL gene in 98 patients (54 AML and 44 MDS). The mutations in VHL gene was examined by direct exons sequence and the methylation status of the promoter region was determined using methylation-specific polymerase chain reaction (MSP). In addition, we examined the expression of HIF-1a in 44 of these patients (25 AML and 18 MDS) through the immunoblotting. VHL mutations were identified only in one patient with AML. However, no mutation was detected in the coding region of the VHL gene in MDS. Meanwhile the methylation of VHL gene was not found in the AML and MDS. But the expression of HIF-1a was found in 10 (66.7%) of 25 patients with AML and 5 (38.5%) of 18 patients with MDS. There is no significant correlation between the expression of HIF-1a and the VHL gene. Our primary date support that the HIF-1a may be involved in the development and progression of AML and MDS, but is not associated with the VHL gene. Disclosures: No relevant conflicts of interest to declare.

Mutations in the VHL gene in sporadic apparently congenital polycythemia

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1591-1595 ◽  
Author(s):  
Yves D. Pastore ◽  
Jaroslav Jelinek ◽  
Sonny Ang ◽  
Yongli Guan ◽  
Enli Liu ◽  
...  
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Elevated Serum ◽  
High Serum ◽  
Compound Heterozygous ◽  
Autosomal Dominant Disorder ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Downstream Target ◽  
History Of

The congenital polycythemic disorders with elevated erythropoietin (Epo) have been until recently an enigma, and abnormality in the hypoxia-sensing pathway has been hypothesized as a possible mechanism. The tumor suppressor von Hippel-Lindau (VHL) participates in the hypoxia-sensing pathway, as it binds to the proline-hydroxylated form of the hypoxia-inducible factor 1α (HIF-1α) and mediates its ubiquitination and proteosomal degradation. The loss of VHL function may result in the accumulation of HIF-1α and overproduction of HIF-1 downstream target genes including Epo. VHL syndrome is an autosomal dominant disorder predisposing to the development of tumors, due to inherited mutations in the VHL gene. Some rare patients with VHL syndrome have polycythemia, which has been attributed to Epo production by a tumor. It was recently found that homozygosity for theVHL Arg200Trp mutation is the cause of Chuvash polycythemia, an autosomal recessive polycythemic disorder characterized by elevated serum Epo and hypersensitivity of erythroid cells to Epo. We evaluated the role of VHL in 8 children with a history of polycythemia and an elevated serum Epo level and found 3 different germline VHL mutations in 4 of them. One child was homozygous for the Arg200Trp VHL mutation, and another compound heterozygous for the Arg200Trp and the Val130Leu mutations. Two children (siblings) were heterozygous for an Asp126Tyr mutation, one of them fulfilling some criteria of VHL syndrome. We propose that mutations of the VHL gene represent an important cause of pediatric sporadic polycythemias with an inappropriately high serum Epo concentration.

scholarly journals Hypoxia-Inducible Factor-2 Alpha as a Novel Target in Renal Cell Carcinoma

2021 ◽  
Vol 8 (2) ◽  
pp. 1-7
Author(s):  
WonSeok W. Choi ◽  
Julia Boland ◽  
Jianqing Lin
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Hypoxia Inducible Factor ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Treat Ment ◽  
Promising Therapeutic Target ◽  
Novel Target ◽  
Endothelial Growth Factor

Hypoxia-inducible factor (HIF), an important mediator of hypoxia response, is implicated in tumorigenesis in the setting of pseudohypoxia, such as in the inactivation of von Hippel–Lindau tumor suppressor protein (pVHL), leading to development and progression of clear cell renal cell carcinoma (ccRCC). Targeting downstream molecules in HIF pathway, such as vascular endothelial growth factor (VEGF), has led to improvement in clinical outcome for patients with advanced ccRCC, but such therapy thus far has been limited by eventual resistance and treat-ment failure. Following the discovery of HIF-2 alpha playing a key role in ccRCC carcinogenesis, inhibitors targeting HIF-2 alpha have been developed and have demonstrated encouraging efficacy and safety profile in clinical trials. This review discusses HIF-2 alpha as a promising therapeutic target for ccRCC.

High-purity magnesium pin enhances bone consolidation in distraction osteogenesis model through activation of the VHL/HIF-1α/VEGF signaling

2020 ◽  
Vol 35 (2) ◽  
pp. 224-236
Author(s):  
Musha Hamushan ◽  
Weijie Cai ◽  
Yubo Zhang ◽  
Tengfei Lou ◽  
Shaoxiang Zhang ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Distraction Osteogenesis ◽  
High Purity ◽  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1Α ◽  
Bone Consolidation ◽  
Endothelial Growth Factor

Distraction osteogenesis has widespread clinical use in the treatment of large bone defects. Nonetheless, the prolonged consolidation period carries the risk of complications. Magnesium-based materials have been shown to promote bone regeneration in fracture healing both in vitro and in vivo. Here, we investigated whether high-purity magnesium could enhance bone formation in distraction osteogenesis. High-purity magnesium pins were placed into the medullary cavity in the rat distraction osteogenesis model. Results showed that the bone volume/total tissue volume, bone mineral density, and mechanical properties of new callus were significantly higher in the high-purity magnesium group compared to stainless steel and control group (p < 0.01). Histological analyses confirmed improved bone consolidation and vascularization in high-purity magnesium group. Further, polymerase chain reaction-array investigation, Western blot, and immunohistochemical results found that vascular endothelial growth factor and hypoxia inducible factor-1α were highly expressed in the high-purity magnesium group, while Von Hippel–Lindau protein was the opposite (p < 0.01). In conclusion, high-purity magnesium implants have the potential to enhance angiogenesis and bone consolidation in the distraction osteogenesis application, and this process might be via the regulation of Von Hippel–Lindau/hypoxia inducible factor-1α/vascular endothelial growth factor signaling.

scholarly journals Astrocyte pVHL and HIF-α isoforms are required for embryonic-to-adult vascular transition in the eye

2011 ◽  
Vol 195 (4) ◽  
pp. 689-701 ◽  
Author(s):  
Toshihide Kurihara ◽  
Peter D. Westenskow ◽  
Tim U. Krohne ◽  
Edith Aguilar ◽  
Randall S. Johnson ◽  
...  
Keyword(s):  
Gene Deletion ◽  
Hypoxia Inducible Factor ◽  
Circulation System ◽  
Growth Factor Signaling ◽  
Targeted Deletion ◽  
Von Hippel Lindau ◽  
Normal Regression ◽  
Persistent Hyperplastic Primary Vitreous ◽  
Vessel Regression ◽  
Endothelial Growth Factor

Successful transition from embryonic to adult circulation is critical for survival of mammalian organisms. This shift occurs in the central cardiovascular circulation and in the eye as oxygen tension increases. However, its regulation is not well understood. We have used combinatorial gene deletion and overexpression assays to assess the effect of astrocyte-targeted deletion of von Hippel–Lindau tumor suppressor (Vhl), hypoxia-inducible factor-αs (Hif-αs), and Vegf on the normal regression of the hyaloidal vessels, the fetal ocular circulation system. Astrocytic Vhl deletion induced accelerated hyaloidal regression and subsequent massive secondary outgrowth. Combinatorial gene deletion involving Vhl, Hif-αs, and Vegf genes revealed that HIF-2α/vascular endothelial growth factor signaling induces secondary outgrowth in Vhl mutants. Conversely, HIF-1α regulated macrophage migration inhibitory factor and promoted macrophage infiltration that accelerates hyaloidal vessel regression. The phenotype observed in Vhl mutants strongly resembles human persistent hyperplastic primary vitreous cases and may provide insights into vascular remodeling mechanisms in other systems.

Sign in / Sign up

Export Citation Format

Share Document