Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Ladroue, Charline; Hoogewijs, David; Gad, Sophie; Carcenac, Romain; Storti, Federica; Barrois, Michel; Gimenez-Roqueplo, Anne-Paule; Leporrier, M; Casadevall, Nicole; Hermine, Olivier; Kiladjian, Jean‐Jacques; Baruchel, André; Fakhoury, Fadi; Paillerets, Brigitte Bressac-de; Feunteun, Jean; Mazure, Nathalie M.; Pouysségur, Jacques; Wenger, Roland H.; Richard, Stéphane; Gardie, Betty

doi:10.3324/haematol.2011.044644

Cited by 47 publications

(84 citation statements)

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“…In these cases, PHDs or other HIF suppression systems might be disrupted in the malignant cells. Recently, hereditary polycythemia has been linked to mutations in the PHD2 and HIF2␣ genes (59)(60)(61)(62)(63), indicating that a PHD-HIF2␣ pathway regulates EPO gene expression in humans.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

Tojo

Sekine

Hirano

et al. 2015

Molecular and Cellular Biology

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f Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1␣ and HIF2␣ under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2␣ or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2␣ activation. HIF2␣ also induces the expression of HIF3␣, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepatic Epo expression regulated by a PHD-HIF2␣-EpoHE cascade in vivo.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

Tojo

Sekine

Hirano

et al. 2015

Molecular and Cellular Biology

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“…Mutations in PHD2 associated with increased risk of tumours have been reported [42] and epigenetic silencing has been proposed for PHD3 [43]. However, based on the striking effect of lactate on activation of PHD2 by 2-oxoglutatrate [28,29], it can be postulated that the activity (and not the expression) of PHD2 may be altered in proportion to the extent of lactate production in tumours, or even within a specific tumour area.…”

Section: Phd2 Integration Of Lactate-driven Angiogenesismentioning

confidence: 99%

Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force

2013

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Abstract. Polet F, Feron O (Universit e catholique de Louvain (UCL), Brussels, Belgium) Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force (Review). J Intern Med 2013; 273: 156-165.Angiogenic endothelial cells and tumour cells can survive under hypoxic conditions and even proliferate and migrate in a low-oxygen environment. In both cell types, high rates of glycolysis (i.e. conversion of glucose to lactate) and glutaminolysis provide most of the required biosynthetic intermediates and energy to support sprouting and cell division without coupling to oxidative phosphorylation. This metabolic preference is observed under hypoxic conditions, but also in situations in which oxygen is present. In the case of tumour cells, this is known as the Warburg effect and is largely governed by oncogenes. In endothelial cells lining tumour blood vessels, the option of respirationindependent metabolism allows the neovasculature to resist the hostile environment of fluctuating oxygen tension (ranging from severe hypoxia to quasi-normal levels of oxygen). In addition, accumulation in tumours of lactate, the end-product of glycolysis, largely contributes to the angiogenic phenotype through inhibition of prolyl hydroxylase 2 and the activation of HIF1a and NFjB. Activation of the latter in a hypoxia-independent manner leads to the increased production of interleukin-8/CXCL8 which drives the autocrine stimulation of endothelial cell proliferation and maturation of neovessels. In conclusion, the addiction of proliferating endothelial cells for glucose and glutamine as fuels and the driving force of lactate to promote angiogenesis provide novel potential treatment options without the disadvantages of conventional anti-angiogenic drugs.

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“…After the first defect of the oxygen-sensing pathway involving the VHL gene was described, 46 different patterns of mutations involving the VHL, PHD, and HIF genes have been described. [47][48][49] The disease is autosomal recessive or dominant, characterized by erythrocytosis, normal-high EPO, frequent headache, and thrombosis. 50 Other causes of inherited erythrocytosis with high EPO include inherited conditions that increase the affinity of hemoglobin for oxygen, including high O 2 affinity hemoglobin disorders and deficiency of 2,3-DPG (I recommend screening for P 50 level on venous blood samples), methemoglobinemia (I recommend measurement of arterial blood gases and pulse oxymetry in case of cyanosis), and cyanotic congenital heart disease (I recommend a cardiology consult).…”

Section: Endogenous Erythroid Colony Formation In Vitromentioning

confidence: 99%

How I treat polycythemia vera

Passamonti

2012

Blood

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Polycythemia vera (PV) is a clonal disorder characterized by unwarranted production of red blood cells. In the majority of cases, PV is driven by oncogenic mutations that constitutively activate the JAK-STAT signal transduction pathway, such as JAK2 V617F, or exon 12 mutations or LNK mutations. Diagnosis of PV is based on the WHO criteria. Diagnosis of post-PV myelofibrosis is established according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria. Different clinical presentations of PV are discussed. Prognostication of PV is tailored to the most frequent complication during follow-up, namely, thrombosis. Age older than 60 years and prior history of thrombosis are the 2 main risk factors for disease stratification. Correlations are emerging between leukocytosis, JAK2(V617F) mutation, BM fibrosis, and different outcomes of PV, which need to be confirmed in prospective studies. In my practice, hydroxyurea is still the "gold standard" when cytoreduction is needed, even though pegylated IFN-alfa-2a and ruxolitinib might be useful in particular settings. Results of phase 1 or 2 studies concerning these latter agents should however be confirmed by the ongoing randomized phase 3 clinical trials. In this paper, I discuss the main problems encountered in daily clinical practice with PV patients regarding diagnosis, prognostication, and therapy. (Blood. 2012;120(2):275-284) IntroductionPolycythemia vera (PV) is a myeloproliferative neoplasm (MPN). 1 The abnormal myeloproliferation of PV is sustained by a constitutively active JAK-STAT signal transduction pathway, caused by the unique V617F mutation within exon 14 (ϳ 95% of PV) 2-5 and by different mutations within exon 12 (ϳ 4% of PV) of the JAK2 gene. 6,7 With lower prevalence, loss of negative regulation of JAK activation caused by LNK mutations (hot spot between codons 208 and 234), 8 or by SOCS mutations 9 or hypermethylation of CpG islands in SOCS1 and SOCS3, 10 have been implicated in PV pathogenesis. The current view suggests that several other cooperating genetic hits might be required. Among others, mutations involving EZH2 11 or TET2, 12 possibly interfering with epigenetic regulatory mechanisms, have been found in approximately 3% and in approximately 16% of JAK2(V617F)-positive PV, respectively.The course of PV is mainly dominated by thrombosis, with an incidence estimated at 18 ϫ 1000 person-years and accounting for 45% of all deaths, but also evolution to myelofibrosis (post-PV MF) and to acute myeloid leukemia (AML), both occurring with an incidence of 5 ϫ 1000 person-years and accounting for 13% of deaths, 13 highlighting the genetic complexity of AML after PV.In this manuscript, I discuss my approach to patients with PV with a focus on specific issues encountered in daily practice regarding diagnosis, prognosis, and treatment. DiagnosisThe median age at presentation is in the sixth decade; patients younger than 50 years of age account for one-third of PV patients. 23 Clinical presentation of PV may be rec...

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Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Cited by 47 publications

References 44 publications

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

Endothelial cell metabolism and tumour angiogenesis: glucose and glutamine as essential fuels and lactate as the driving force

How I treat polycythemia vera

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