scholarly journals FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL

Blood ◽  
2019 ◽  
Vol 133 (8) ◽  
pp. 830-839 ◽  
Author(s):  
Viola Close ◽  
William Close ◽  
Sabrina Julia Kugler ◽  
Michaela Reichenzeller ◽  
Deyan Yordanov Yosifov ◽  
...  
Keyword(s):  
Target Gene ◽  
Hypoxia Inducible Factor ◽  
Gene Activation ◽  
Lymphocytic Leukemia ◽  
Negative Regulator ◽  
Missense Mutations ◽  
Protein Levels ◽  
In Silico Modeling ◽  
Functional Consequences ◽  
Wd40 Domain

Abstract NOTCH1 is mutated in 10% of chronic lymphocytic leukemia (CLL) patients and is associated with poor outcome. However, NOTCH1 activation is identified in approximately one-half of CLL cases even in the absence of NOTCH1 mutations. Hence, there appear to be additional factors responsible for the impairment of NOTCH1 degradation. E3-ubiquitin ligase F-box and WD40 repeat domain containing-7 (FBXW7), a negative regulator of NOTCH1, is mutated in 2% to 6% of CLL patients. The functional consequences of these mutations in CLL are unknown. We found heterozygous FBXW7 mutations in 36 of 905 (4%) untreated CLL patients. The majority were missense mutations (78%) that mostly affected the WD40 substrate binding domain; 10% of mutations occurred in the first exon of the α-isoform. To identify target proteins of FBXW7 in CLL, we truncated the WD40 domain in CLL cell line HG-3 via clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9). Homozygous truncation of FBXW7 resulted in an increase of activated NOTCH1 intracellular domain (NICD) and c-MYC protein levels as well as elevated hypoxia-inducible factor 1-α activity. In silico modeling predicted that novel mutations G423V and W425C in the FBXW7-WD40 domain change the binding of protein substrates. This differential binding was confirmed via coimmunoprecipitation of overexpressed FBXW7 and NOTCH1. In primary CLL cells harboring FBXW7 mutations, activated NICD levels were increased and remained stable upon translation inhibition. FBXW7 mutations coincided with an increase in NOTCH1 target gene expression and explain a proportion of patients characterized by dysregulated NOTCH1 signaling.

scholarly journals NOTCH1 Signaling Is Activated in CLL By Mutations of FBXW7 and Low Expression of USP28 at 11q23

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 946-946 ◽  
Author(s):  
Viola Close ◽  
William Close ◽  
Sabrina Julia Kugler ◽  
Michaela Reichenzeller ◽  
Deyan Yordanov Yosifov ◽  
...  
Keyword(s):  
Gene Expression ◽  
In Silico ◽  
Research Funding ◽  
Target Gene ◽  
Negative Regulator ◽  
Novel Mutations ◽  
Target Gene Expression ◽  
In Silico Modeling ◽  
Wd40 Domain ◽  
Support Research

Abstract Background Oncogenic proteins can be stabilized either via genetic mutations or via defects in the ubiquitin ligating- and degradation machinery. NOTCH1 protein stability is affected by genetic mutations in approximately 10% of chronic lymphocytic leukemia (CLL) patients and mutations are associated with a worse prognosis. Yet, even in the absence of NOTCH1 mutations, NOTCH1 is activated in almost half of all CLL patients. Aims In order to shed light on NOTCH1 activation in CLL, we analyzed the impact of its modulator, the E3-ubiquitin ligase FBXW7 and the deubiquitinase USP28 that is a negative regulator of FBXW7 and is located in chromosomal band 11q23. Methods FBXW7 mutation analysis was performed via targeted next generation sequencing from a total of 905 patients. In silico modeling of potential substrate binding to the mutated FBXW7 was performed by the use of PolyPhen-2 and validated via co-immunoprecipitation of overexpressed mutated FBXW7 and NOTCH1 wild type proteins. Accumulation of FBXW7 substrates was tested via Western blot in CRISPR/Cas9 induced FBXW7 mutated HG-3 CLL cell lines and in FBXW7 mutated primary CLL cells, identifying the transcription factor NOTCH1 as FBXW7 target. Expression of NOTCH1 target genes were analyzed in FBXW7 mutated CLL cases via gene expression profiling (n=4) and RT-qPCR (n=19). In an independent cohort, USP28 and NOTCH1 target gene expression was analyzed in a total of 285 patients via gene expression profiling. Results Heterozygous FBXW7 mutations were identified in 41/905 (4.5%) CLL patients. The majority were missense mutations (78%) that mostly affected the WD40 substrate binding domain, while an additional 10% of mutations were located on the first exon of the abundantly expressed FBXW7 α-isoform. We identified substrate targets of FBXW7 in CLL via the generation of a truncation of the WD40 domain of FBXW7 in the CLL cell line HG-3 using CRISPR/Cas9, identifying NOTCH1 as an FBXW7 target. In silico modeling of FBXW7 mutations on protein binding predicted that novel mutations within the WD40 domain affected substrate recognition capacity of FBXW7. Interestingly, modeling predicted W425C and a new hotspot mutation G423V (found in 3/905 of CLL cases) to ablate NOTCH1 binding while the mutation A503V was predicted not to impair binding of NOTCH1 to FBXW7. The in silico modeling was confirmed by co-immunoprecipitation experiments of overexpressed NOTCH1 and FBXW7 and further revealed that mutations within the α-isoform specific N-terminus T15VR and V154I still enabled NOTCH1 binding. Intriguingly, in primary CLL cells FBXW7 mutations correlated with an increase in NOTCH1 levels that remained stable even upon inhibition of translation, underlining the enhanced protein stabilization by FBXW7 mutations. Furthermore, FBXW7 mutations in CLL resulted in an increased NOTCH1 target gene expression. FBXW7 activity is not only modulated by gene mutations, but also by the deubiquitinase USP28 which is localized in the recurrently deleted region 11q22-q23 close to the ATM tumor suppressor gene. We hypothesized that USP28 would impact on FBXW7 activity and thus on NOTCH1 stability and activity. In line with this concept we found that in primary cells from a cohort of 285 CLL patients, low USP28 expression significantly correlated with increased NOTCH1 target gene expression, independent of the 11q deletion status of the patients where USP28 is localized. Discussion In CLL patient cells we have identified novel mutations within the WD40 binding domain of FBXW7 in addition to the common hot spot mutations (R465, R479, R505). Amongst these novel mutations, G423V and W425C are recurrent and result in decreased binding of the FBXW7 substrate NOTCH1 and hence in an accumulation and induction of NOTCH1 activity. Furthermore, expression of USP28, the negative regulator of FBXW7, significantly correlated with increased NOTCH1 target gene expression. Hence, our findings uncover modulation of NOTCH1 in CLL via the FBXW7-USP28-NOTCH1 axis (Figure 1) in addition to genomic NOTCH1 modification, thus explaining the high proportion of CLL cases that harbor an activation of NOTCH1 leading to more aggressive disease. Disclosures Tausch: AbbVie: Consultancy, Other: Travel grants; Celgene: Consultancy, Other: Travel grants; Gilead: Consultancy, Other: Travel grants. Döhner:AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding. Stilgenbauer:Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding.

scholarly journals TfR1 interacts with the IKK complex and is involved in IKK–NF-κB signalling

2012 ◽  
Vol 449 (1) ◽  
pp. 275-284 ◽  
Author(s):  
Niall S. Kenneth ◽  
Sharon Mudie ◽  
Sanne Naron ◽  
Sonia Rocha
Keyword(s):  
Target Gene ◽  
Gene Activation ◽  
Nuclear Factor Κb ◽  
Gene Promoters ◽  
Protein Levels ◽  
Transferrin Receptor 1 ◽  
The Family ◽  
Ikk Complex ◽  
Factor Α ◽  
Necrosis Factor

The IKK [inhibitor of NF-κB (nuclear factor κB) kinase] complex has an essential role in the activation of the family of NF-κB transcription factors in response to a variety of stimuli. To identify novel IKK-interacting proteins, we performed an unbiased proteomics screen where we identified TfR1 (transferrin receptor 1). TfR1 is required for transferrin binding and internalization and ultimately for iron homoeostasis. TfR1 depletion does not lead to changes in IKK subunit protein levels; however, it does reduce the formation of the IKK complex, and inhibits TNFα (tumour necrosis factor α)-induced NF-κB-dependent transcription. We find that, in the absence of TfR1, NF-κB does not translocate to the nucleus efficiently, and there is a reduction in the binding to target gene promoters and consequentially less target gene activation. Significantly, depletion of TfR1 results in an increase in apoptosis in response to TNFα treatment, which is rescued by elevating the levels of RelA/NF-κB. Taken together, these results indicate a new function for TfR1 in the control of IKK and NF-κB. Our data indicate that IKK–NF-κB responds to changes in iron within the cell.

scholarly journals Sirtuin-7 Inhibits the Activity of Hypoxia-inducible Factors

2013 ◽  
Vol 288 (29) ◽  
pp. 20768-20775 ◽  
Author(s):  
Maimon E. Hubbi ◽  
Hongxia Hu ◽  
Kshitiz ◽  
Daniele M. Gilkes ◽  
Gregg L. Semenza
Keyword(s):  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Negative Regulator ◽  
Molecular Function ◽  
Hypoxia Inducible Factors ◽  
Lysosomal Degradation ◽  
Transcriptional Responses ◽  
Protein Levels ◽  
Catalytic Function ◽  
Prolyl Hydroxylation

Hypoxia-inducible factor (HIF) 1 and HIF-2 are heterodimeric proteins composed of an oxygen-regulated HIF-1α or HIF-2α subunit, respectively, and a constitutively expressed HIF-1β subunit, which mediate adaptive transcriptional responses to hypoxia. Here, we report that Sirt7 (sirtuin-7) negatively regulates HIF-1α and HIF-2α protein levels by a mechanism that is independent of prolyl hydroxylation and that does not involve proteasomal or lysosomal degradation. The effect of Sirt7 was maintained in the presence of the sirtuin inhibitor nicotinamide and upon deletion or mutation of its deacetylase domain, indicating a non-catalytic function. Knockdown of Sirt7 led to an increase in HIF-1α and HIF-2α protein levels and an increase in HIF-1 and HIF-2 transcriptional activity. Thus, we identify a novel molecular function of Sirt7 as a negative regulator of HIF signaling.

scholarly journals p73: a Positive or Negative Regulator of Angiogenesis, or Both?

2015 ◽  
Vol 36 (6) ◽  
pp. 848-854 ◽  
Author(s):  
Kanaga Sabapathy
Keyword(s):  
Blood Vessel ◽  
Hypoxia Inducible Factor ◽  
Gene Activation ◽  
Negative Regulator ◽  
Positive Role ◽  
Blood Vessel Formation ◽  
Cellular Survival ◽  
Vessel Formation ◽  
Cellular Context ◽  
Negative Role

The role of p73, the homologue of the tumor suppressor p53, in regulating angiogenesis has recently been extensively investigated, resulting in the publication of five articles. Of these, two studies suggested a suppressive role, while the others implied a stimulatory role for the p73 isoforms in regulating angiogenesis. A negative role for TAp73, the full-length form that is often associated with tumor suppression, in blood vessel formation, is consistent with its general attributes and was proposed to be effected indirectly through the degradation of hypoxia-inducible factor 1α (HIF1-α), the master angiogenic regulator. In contrast, a positive role for TAp73 coincides with its recently understood role in supporting cellular survival and thus tumorigenesis, consistent with TAp73 being not-mutated but rather often overexpressed in clinical contexts. In the latter case, TAp73 expression was induced by hypoxia via HIF1-α, and it appears to directly promote angiogenic target gene activation and blood vessel formation independent of HIF1-α. This mini review will provide an overview of these seemingly opposite recent findings as well as earlier data, which collectively establish the definite possibility that TAp73 is indeed capable of both promoting and inhibiting angiogenesis, depending on the cellular context.

scholarly journals DEAD Box Protein Family Member DDX28 Is a Negative Regulator of Hypoxia-Inducible Factor 2α- and Eukaryotic Initiation Factor 4E2-Directed Hypoxic Translation

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Sonia L. Evagelou ◽  
Olivia Bebenek ◽  
Erin J. Specker ◽  
James Uniacke
Keyword(s):  
Family Member ◽  
Mammalian Cells ◽  
Hypoxia Inducible Factor ◽  
Protein Family ◽  
Negative Regulator ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Protein Levels ◽  
Oxygen Homeostasis ◽  
Dead Box

ABSTRACT Hypoxia is a deficiency in oxygen delivery to tissues and is connected to physiological and pathophysiological processes such as embryonic development and cancer. The master regulators of oxygen homeostasis in mammalian cells are the heterodimeric hypoxia-inducible transcription factors 1 and 2 (HIF-1 and HIF-2, respectively). The oxygen-labile HIF-2α subunit has been implicated not only in transcription but also as a regulator of eukaryotic initiation factor 4E2 (eIF4E2)-directed hypoxic translation. Here, we have identified the DEAD box protein family member DDX28 as an interactor and negative regulator of HIF-2α that suppresses HIF-2α’s ability to activate eIF4E2-directed translation. Stable silencing of DDX28 via short hairpin RNA (shRNA) in hypoxic human U87MG glioblastoma cells caused an increase of eIF4E2 binding to the m7GTP cap structure and the translation of eIF4E2 target mRNAs (including the HIF-2α mRNA itself). DDX28 depletion elevated nuclear and cytoplasmic HIF-2α protein, but HIF-2α transcriptional activity did not increase, possibly due to its already high nuclear abundance in hypoxic control cells. Depletion of DDX28 conferred a proliferative advantage to hypoxic, but not normoxic, cells. DDX28 protein levels are reduced in several cancers, including gliomas, relative to levels in normal tissue. Therefore, we uncover a regulatory mechanism for this potential tumor suppressor in the repression of HIF-2α- and eIF4E2-mediated translation activation of oncogenic mRNAs.

scholarly journals The NADPH Oxidase Subunit NOX4 Is a New Target Gene of the Hypoxia-inducible Factor-1

2010 ◽  
Vol 21 (12) ◽  
pp. 2087-2096 ◽  
Author(s):  
Isabel Diebold ◽  
Andreas Petry ◽  
John Hess ◽  
Agnes Görlach
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Target Gene ◽  
Hypoxia Inducible Factor ◽  
Oxygen Species ◽  
Protein Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Signaling Axis ◽  
Pulmonary Artery Smooth Muscle ◽  
Responsive Element

NADPH oxidases are important sources of reactive oxygen species (ROS), possibly contributing to various disorders associated with enhanced proliferation. NOX4 appears to be involved in vascular signaling and may contribute to the response to hypoxia. However, the exact mechanisms controlling NOX4 levels under hypoxia are not resolved. We found that hypoxia rapidly enhanced NOX4 mRNA and protein levels in pulmonary artery smooth-muscle cells (PASMCs) as well as in pulmonary vessels from mice exposed to hypoxia. This response was dependent on the hypoxia-inducible transcription factor HIF-1α because overexpression of HIF-1α increased NOX4 expression, whereas HIF-1α depletion prevented this response. Mutation of a putative hypoxia-responsive element in the NOX4 promoter abolished hypoxic and HIF-1α–induced activation of the NOX4 promoter. Chromatin immunoprecipitation confirmed HIF-1α binding to the NOX4 gene. Induction of NOX4 by HIF-1α contributed to maintain ROS levels after hypoxia and hypoxia-induced proliferation of PASMCs. These findings show that NOX4 is a new target gene of HIF-1α involved in the response to hypoxia. Together with our previous findings that NOX4 mediates HIF-1α induction under normoxia, these data suggest an important role of the signaling axis between NOX4 and HIF-1α in various cardiovascular disorders under hypoxic and also nonhypoxic conditions.

Genetic variation in CXCR4 and risk of chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 114 (23) ◽  
pp. 4843-4846 ◽  
Author(s):  
Dalemari Crowther-Swanepoel ◽  
Mobshra Qureshi ◽  
Martin J. S. Dyer ◽  
Estella Matutes ◽  
Claire Dearden ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Missense Mutations ◽  
Common Variation ◽  
Coding Regions ◽  
Genome Wide ◽  
A Genome ◽  
Functional Consequences ◽  
Gene Maps

Abstract A genome-wide linkage scan has provided evidence for a chronic lymphocytic leukemia (CLL) susceptibility locus at 2q21 to which the chemokine receptor CXCR4 gene maps. Recent data provide some evidence for common variation in CXCR4 according to the polymorphic variant rs2228014 defining CLL risk. To examine the role of genetic variation in CXCR4 on CLL risk, we screened 188 familial CLL cases and 213 controls for germline mutations in the coding regions of CXCR4 and genotyped rs2228014 in 1058 CLL cases and 1807 controls. No association between rs2228014 and risk of CLL was seen (P = .83). One truncating (W195X) and 2 missense mutations with possible functional consequences (V139I and G335S) were identified among 186 familial cases and 0 in 213 controls sequenced. Our analysis provides no evidence that common variation in CXCR4 defined by rs228014 influences the risk of CLL, but that functional coding mutations in CXCR4 may contribute to familial CLL.

scholarly journals CITED2 Restrains Proinflammatory Macrophage Activation and Response

2017 ◽  
Vol 38 (5) ◽  
Author(s):  
Gun-Dong Kim ◽  
Riku Das ◽  
Xiaoquan Rao ◽  
Jixin Zhong ◽  
Jeffrey A. Deiuliis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Hypoxia Inducible Factor ◽  
Myeloid Cell ◽  
Negative Regulator ◽  
Peroxisome Proliferator ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anti Inflammatory

ABSTRACT Macrophages are strategically distributed in mammalian tissues and play an essential role in priming the immune response. However, macrophages need to constantly strike a balance between activation and inhibition states to avoid a futile inflammatory reaction. Here, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage proinflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPARγ) activation and attendant select anti-inflammatory gene expression in macrophages. More importantly, deficiency of CITED2 resulted in significant attenuation of rosiglitazone-induced PPARγ activity, PPARγ recruitment to target gene promoters, and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened proinflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1α) protein in macrophages. Further, overexpression of Egln3 or inhibition of HIF1α in Cited2 -deficient macrophages completely reversed elevated proinflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid cell-specific deletion of Cited2 were highly susceptible to endotoxin-induced sepsis symptomatology and mortality. Collectively, our observations identify CITED2 as a novel negative regulator of macrophage proinflammatory activation that protects the host from inflammatory insults.

scholarly journals A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

2019 ◽  
Vol 77 (18) ◽  
pp. 3627-3642 ◽  
Author(s):  
Jussi-Pekka Tolonen ◽  
Minna Heikkilä ◽  
Marjo Malinen ◽  
Hang-Mao Lee ◽  
Jorma J. Palvimo ◽  
...  
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Negative Regulator ◽  
Luciferase Reporter ◽  
Transcription Activator ◽  
Promoter Regions ◽  
Α Subunit ◽  
Hypoxia Response ◽  
Protein Levels ◽  
Oxygen Homeostasis

AbstractHypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis with hundreds of hypoxia-inducible target genes. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered a negative regulator of the hypoxia response pathway. However, the human HIF3A mRNA is subject to complex alternative splicing. It was recently shown that the long HIF-3α variants can form αβ dimers that possess transactivation capacity. Here, we show that overexpression of the long HIF-3α2 variant induces the expression of a subset of genes, including the erythropoietin (EPO) gene, while simultaneous downregulation of all HIF-3α variants by siRNA targeting a shared HIF3A region leads to downregulation of EPO and additional genes. EPO mRNA and protein levels correlated with HIF3A silencing and HIF-3α2 overexpression. Chromatin immunoprecipitation analyses showed that HIF-3α2 binding associated with canonical hypoxia response elements in the promoter regions of EPO. Luciferase reporter assays showed that the identified HIF-3α2 chromatin-binding regions were sufficient to promote transcription by all three HIF-α isoforms. Based on these data, HIF-3α2 is a transcription activator that directly regulates EPO expression.

scholarly journals Isolated Erythrocytosis Associated With 3 Novel Missense Mutations in the EGLN1 Gene

2020 ◽  
Vol 8 ◽  
pp. 232470962094725
Author(s):  
Joseph A. Moore ◽  
Maimon E. Hubbi ◽  
Chenliang Wang ◽  
Yingfei Wang ◽  
Weibo Luo ◽  
...  
Keyword(s):  
Protein Stability ◽  
Cultured Cells ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Gene Encoding ◽  
Protein Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Prolyl Hydroxylase Domain

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.

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