The n e w e ng l a n d j o u r na l of m e dic i n e

brief REPORT

PHD2 Mutation and Congenital

Erythrocytosis with Paraganglioma
Charline Ladroue, M.Sc., Romain Carcenac, B.Sc., Michel Leporrier, M.D.,
Sophie Gad, Ph.D., Claire Le Hello, M.D., Françoise Galateau-Salle, M.D.,
Jean Feunteun, Ph.D., Jacques Pouysségur, Ph.D., Stéphane Richard, M.D., Ph.D.,
and Betty Gardie, Ph.D.

Sum m a r y

Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-
inducible factor (HIF) that induces expression of genes involved in angiogenesis,
erythropoiesis, and cell metabolism, proliferation, and survival. Germ-line mutations
in the prolyl hydroxylase domain 2 gene (PHD2) have been reported in patients with
familial erythrocytosis but not in association with tumors. We describe a patient with
erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2
mutation. This mutation affects PHD2 function and stabilizes HIF-α proteins. In ad-
dition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that
PHD2 could be a tumor-suppressor gene.

A 
ccurate regulation of oxygen homeostasis is essential for sur- From Génétique Oncologique, Ecole Pra-
vival. HIF, a transcription factor that activates hypoxia-inducible genes, is tique des Hautes Etudes (EPHE) and
Centre National de la Recherche Scienti-
conserved during evolution from worms to vertebrates. It plays a central role in fique (CNRS) (FRE 2939), Institut de
oxygen homeostasis during embryonic development and postnatal life but is also in- Cancérologie Gustave Roussy, Villejuif
volved in pathologic processes such as erythrocytosis, tumor development, angio- (C. Ladroue, R.C., S.G., J.F., S.R., B.G.);
Faculté de Médecine Paris-Sud, Univer-
genesis, and metastases.1 sité Paris-Sud (C. Ladroue, R.C., S.G.,
HIF is an alpha/beta heterodimer consisting of a tightly regulated alpha subunit S.R., B.G.), and Centre Pilote Tumeurs
(1α, 2α, or 3α) and a constitutively expressed beta subunit. Under normoxic condi- Rares, Institut National du Cancer and
Assistance Publique–Hôpitaux de Paris,
tions, HIF-α subunits are hydroxylated by dioxygenases that use oxygen as a co­ Service d’Urologie, Centre Hospitalier
substrate.2,3 The PHD proteins (also called EGLN proteins) are dioxygenases that Universitaire de Bicêtre (S.R.) — both in
hydroxylate key proline residues of HIF-α, allowing for the attachment of HIF-α Le Kremlin Bicêtre; Service d’Hématologie
Clinique (M.L.), Service de Chirurgie Tho-
to the von Hippel–Lindau (VHL) tumor-suppressor protein, part of a complex that racique et Cardio-Vasculaire (C. Le Hello),
leads to the ubiquitination and degradation of HIF-α in the proteasome. In mam- and Laboratoire d’Anatomie et Cytologie
malian cells, there is a family of PHD proteins (PHD1, PHD2, and PHD3), among Pathologiques (F.G.-S.), Centre Hospita-
lier Universitaire, Caen; Institute of De-
which PHD2 (also called EGLN1) seems to be the critical oxygen sensor that tags velopmental Biology and Cancer Research,
HIF-1α for destruction.2,4 In addition, factor-inhibiting HIF hydroxylates the aspar- CNRS (UMR 6543) University of Nice,
agine residue in the C-terminal domain of HIF, which blocks the attachment of Nice (J.P.); and Service de Néphrologie,
Hôpital Necker, Paris (S.R.) — all in France.
HIF to an essential transcriptional coactivator.5 Address reprint requests to Dr. Richard
Germ-line mutations in genes involved in the HIF pathway have been described at Génétique Oncologique EPHE, Faculté
in association with syndromes that predispose patients to either tumors or familial de Médecine Paris-Sud, 63 Rue Gabriel
Péri, 94276 Le Kremlin-Bicêtre, France,
polycythemia. The most frequent alterations affect the VHL tumor-suppressor gene; or at stephane.richard@u-psud.fr.
heterozygous germ-line mutations of VHL cause VHL disease.6 This autosomal domi-
nant condition predisposes patients to multiple vascularized tumors, including he- Ms. Ladroue and Mr. Carcenac contributed
equally to this article.
mangioblastomas of the central nervous system and retina, clear-cell renal-cell carci-
nomas, pheochromocytomas, endocrine pancreatic tumors, and endolymphatic sac N Engl J Med 2008;359:2685-92.
tumors. In contrast, a homozygous 598C→T (R200W) germ-line mutation of VHL Copyright © 2008 Massachusetts Medical Society.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

causes Chuvash congenital polycythemia, an au-
tosomal recessive disease reported first in resi-
dents of the Chuvash Autonomous Republic of
the Russian Federation.7 Homozygous carriers of
the R200W mutation have erythrocytosis, with in-
creased erythropoietin production. Remarkably,
carriers of the R200W mutation are not unduly
susceptible to cancer. Heterozygous germ-line mu-
tations in the PHD2 gene and the gene for HIF-2α
(HIF2A) have been found in patients with familial
erythrocytosis due to an elevated erythropoietin
level, but tumors have not been reported.8-11
Germ-line mutations in genes encoding two
mitochondrial enzymes operating in the Krebs
cycle, fumarate hydratase (FH) and succinate de-
hydrogenase (SDHB, SDHC, and SDHD), have been
implicated in the development of the hereditary
leiomyomatosis and renal-cell cancer syndrome
and the hereditary paraganglioma–pheochromo-
cytoma syndrome.12 In tumors deficient in FH and
SDH, accumulation of the substrates (fumarate and
succinate) inhibits PHD function and in this way
causes overexpression of HIF.
We investigated the main genes of the HIF
pathway in a patient with congenital erythrocyto-
sis and recurrent abdominal paraganglioma.
C a se R ep or t
The patient was referred to us in 1988, when he was
30 years old and had a hematocrit value within the
upper end of the normal range (Table 1). Clinical
and laboratory workups confirmed the diagnosis
of erythrocytosis, but both routine and specialized
tests failed to identify a specific cause. The eryth-
ropoietin-dependent in vitro growth of erythroid
colonies ruled out the diagnosis of polycythemia
vera. Phlebotomy was initiated, to maintain the he-
matocrit value below 45%. In addition, mild hy-
pertension was treated with atenolol. Because the
mean corpuscular volume and ferritin level re-
mained normal on follow-up, despite the phlebot-

Table 1. Diagnostic Tests for Erythrocytosis in the Patient at the Time of Diagnosis (1988).

Test Value or Finding

Complete blood count
Erythrocytes (per mm3) 6,200,000
Hematocrit (%) 61.6
Hemoglobin (g/dl) 20.2
Leukocytes (per mm3)* 6800
Platelets (per mm3) 162,000
Isotopic blood volume (ml)†
Red cells 3065
Plasma 2647
Whole blood 5742
O2 saturation (%) 96.5
Findings on abdominal ultrasonography No abnormality of the kidney, liver,
and computed tomography spleen, or other organ
Histologic features of bone marrow Erythroid hyperplasia, without fibrosis
Erythropoietin (mU/ml)‡ 18
2,3-Diphosphoglycerate (μM/g hemoglobin)§ 16
P50 value (mm Hg)¶ 31
Erythropoietin-dependent erythroid colony growth in bone marrow Yes

* The differential count was normal.

† Red-cell volume and plasma volume were measured with the use of 99mTc labeling and 125I-albumin labeling, respec-
tively. Normal red-cell, plasma, and whole-blood volumes are 2160, 3240, and 5400 ml, respectively.
‡ Erythropoietin was measured with the use of the radioimmunoassay. The normal range is 5 to 25 mU per milliliter.
§ The mean (±SD) normal level of 2,3-diphosphoglycerate is 15±2 μM per gram of hemoglobin.
¶ The P50 value is the partial pressure of oxygen at 50% dissociation, according to the oxygen-binding curve. The mean
(±SD) normal value is 31±1 mm Hg.

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 brief report

A B

H374R/ Wild type/ Wild type/

wild type wild type wild type
(proband)

Wild type/
wild type

Figure 1. PHD2 Genotypes of the Patient and His Family, and Histopathological Features of the Tumor.
The pedigree of the patient’s familyICM AUTHOR:
is shown Ladroue
in Panel A. Squares representRETAKE 1st
male family members, circles female
2nd
family members, and slashes deceased
REG F family members;
FIGURE: 1 of 3 the solid square denotes the presence of erythrocytosis
3rd
and abdominal paraganglioma in the CASEproband. Genotypes for the PHD2 gene are shown for each family member
Revised
tested. Panel B, top, shows a microscopical
EMail image of the tumor
Line (hematoxylin
4-C and
SIZE eosin), revealing typical patterns
of a paraganglioma with an organoid ARTIST: ts(Zellballen)
arrangement H/T of tumor
H/T cells with pink granular cytoplasm and with
Enon 33p9
nuclear pleomorphism and vascular invasion. Immunocytochemical Combo images show cytoplasmic expression of chro-
mogranin A by tumor cells (bottom left), as wellAUTHOR, PLEASE NOTE:
as sustentacular cells (indicated by arrows) with uniform reactivity
Figure has been redrawn and type has been reset.
to S-100 protein (bottom right). Please check carefully.

JOB: 35925 ISSUE: 12-18-08

omy regimen, the patient was evaluated for, and
was found to be homozygous for, the C282Y hot-
spot mutation in the hemochromatosis gene HFE,
which has no causal relationship to polycythe­mia.13
All members of the proband’s family were tested,
and his brother was also found to be homozygous
for the C282Y mutation (and is now undergoing
treatment for hemochromatosis). Neither erythro-
cytosis nor tumor was found in any family mem-
ber other than the proband (Fig. 1A).
Results of abdominal ultrasonography, repeated
annually, remained normal until 2001, when the
patient was 43 years old. A para-aortic mass was
discovered on computed tomography (CT) and con-
firmed on magnetic resonance imaging. A solid,
encapsulated, red-brown tumor, 3.5 by 3.5 cm, was
resected, and the sections revealed two additional
small nodules, 13 mm and 8 mm in diameter. On
microscopical analysis, the tumor had typical fea-
tures of a paraganglioma (Fig. 1B).
Subsequently, the blood pressure returned to
normal, atenolol was discontinued, and the hema-
tocrit value became stabilized within the normal
range without further phlebotomy. In 2003, how-
ever, urinary excretion of metanephrines was in
the upper end of the normal range, and the hema-
tocrit value rose, raising suspicion of recurrence
of the tumor, which was substantiated by 131I-
metaiodobenzylguanidine scintigraphy scanning
in 2004.
During a second operation, the tumor, which
was histologically similar to the previous one, was
completely resected. The serum erythropoietin
level (normal range, 5 to 25 mU per milliliter) was
48 mU per milliliter before the resection and 32 mU
per milliliter 8 days after the resection. A relation
between the erythrocytosis and erythropoietin
production by the tumor was ruled out, however,
since erythropoietin messenger RNA was not
found on gene-expression assays (Taqman as-
say, with human hepatocellular carcinoma cells
[Hep3B cells] and an erythropoietin-producing tu-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A
Mutation c.1121A→G (p.H374R)

C A A C C C T C A T G A A G T A C

Reference DNA

C A A C C C T C R T G A A G T A C

Patient’s germ-line DNA

C A A C C C T C R T G A A G T A C

Tumor DNA

Centromere PHD2 Telomere

D1S2877 D1S2833 D1S251 D1S2709 D1S2785 D1S2836

Germ-
line
DNA

Tumor
DNA

AIR 0.31 0.33 0.38 0.39 0.35 0.34

Figure 2. The PHD2 Mutation and Results of Loss-of-Heterozygosity Analysis of the Tumor.
AUTHOR: Ladroue RETAKE 1st
Panel A shows a sequence chromatogram
ICM of PHD2 exon 3 in the area of the mutated 2nd
nucleotide. Panel B shows the
FIGURE: 2 of 3
results of loss-of-heterozygosity analysis on germ-line and tumor DNA. Six microsatellite
REG F
3rd markers, spanning 57 Mb
of the 1q42 region, were investigated.
CASETheir positions relative to the centromereRevised and the telomere are indicated
EMail ratios (AIRs) wereLine
(drawing not to scale). Allelic imbalance 4-Cby dividing
calculated SIZEthe ratio of the peak heights of the
ARTIST: ts
the peak heights of theH/T
two germ-line alleles by the ratio ofEnon two
Combo
H/Talleles.33p9
tumor An AIR value of less than 0.5 indicates
loss of heterozygosity, shown by all the markers we tested. For a version of Panel B showing the specifications of
AUTHOR, PLEASE NOTE:
each peak, see the Supplementary Appendix (available with the full text of this article at www.nejm.org).
Figure has been redrawn and type has been reset.
Please check carefully.

JOB: 35925 ISSUE: 12-18-08

mor associated with secondary polycythemia as
controls) (data not shown). From 2004 through the
time of publication of this article, the patient’s
clinical status has remained unchanged, with a
slight elevation of hematocrit and blood pressure,
both requiring treatment with phlebotomy and
antihypertensive drugs. Repeated CT and 131I-
metaiodobenzylguanidine scanning have not de-
tected tumor recurrence, although urinary excre-
tion of metanephrines has remained at twice the
upper limit of the normal range during this pe-
riod. The possibilities of VHL disease or the he-
reditary paraganglioma–pheochromocytoma syn-
drome were ruled out through routine genetic
testing: no germ-line mutation was identified in
the VHL, SDHB, SDHC, or SDHD genes.

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 brief report

Me thods PHD2 (wild type, or H374R mutant) expression

vector (5 to 125 ng). Luciferase activity was mea-
DNA Sequencing and Loss-of-Heterozygosity sured 24 hours after transfection with the use of
Analysis a Dual-Luciferase Reporter Assay System (Pro-
After receiving approval from our local ethics com- mega). For immunoblotting, 15-μl aliquots of
mittee and obtaining written informed consent the lysates used in luciferase assays were run,
from the proband and all family members, blood and anti-HA (F7) antibody (Tebu) was used.
samples were collected for genetic analysis. Ge-
nomic DNA was extracted from peripheral blood R e sult s
and paraganglioma and purified on a spin column
(Qiagen). Screening for mutations in the PHD2 gene Sequencing and Loss-of-Heterozygosity
was performed by means of direct sequencing (in- Analysis
volving a BigDye Terminator v3.1 Kit and an ABI We sequenced germ-line DNA obtained from the
3730 Genetic Analyzer, both from Applied Bio- patient for genes that could be implicated in con-
systems). Sequence data were aligned using 4Peaks genital polycythemia associated with a high se-
software (http://mekentosj.com/4peaks). Sequenc- rum erythropoietin level: PHD1, PHD2, PHD3, and
es of all primers used in this study are given in HIF2A. We identified a unique c.1121A→G (p.H374R)
the Supplementary Appendix, available with the heterozygous variation in the PHD2 gene (Fig. 2A).
full text of this article at www.nejm.org. DNA The absence of this variant in a control population
samples from normal persons were screened for (in which 280 alleles were tested) ruled out a rare
the c.1121A→G mutation (with 280 alleles tested). polymorphism. None of the three first-degree rela-
In silico prediction of the deleterious effect of the tives of the patient were carriers of the PHD2 mu-
mutant was performed through the PolyPhen Web tation. DNA of the patient’s tumor was sequenced
site (http://genetics.bwh.harvard.edu/pph) and the for the PHD2 gene, and the mutant allele was de-
Panther Web site (www.pantherdb.org). tected (Fig. 2A). Interestingly, the chromatogram
For loss-of-heterozygosity analysis, six micro- at position 1121 revealed predominantly the mu-
satellite markers flanking the PHD2 gene (located tant allele, indicating a loss-of-heterozygosity of
at 1q42.1) were analyzed: D1S2877, D1S2833, PHD2; the residual signal for the wild-type allele
D1S251, D1S2709, D1S2785, and D1S2836 (ABI could be accounted for through contamination by
PRISM Linkage Mapping Set, Applied Biosystems). normal tissue. Loss of heterozygosity was con-
Amplification was performed with the use of the firmed through microsatellite analysis of the PHD2
Multiplex PCR Master Mix (Qiagen), according to region, which showed monozygosity for all the
the manufacturer’s instructions. Amplified frag- markers tested (Fig. 2B).
ments were run on the genetic analyzer (ABI 3730).
Data were analyzed with the use of GeneMapper Functional Studies
software (Applied Biosystems). Consequences of the amino acid change were ana-
lyzed by computer programs, and the PolyPhen
Functional Analysis and Panther Web sites predicted that the changes
The H374R PHD2 mutation was inserted into a observed would have a negative effect on protein
pcDNA3-HA-PHD2 vector by means of site-directed function. H374 is a highly conserved residue, pres-
mutagenesis (Promega). Luciferase assays were per- ent in various life forms (from worms to flies to
formed on human embryonic kidney 293T cells humans) and even prokaryotic pathogens (Fig. 3A).
cultured in Dulbecco’s modified Eagle’s medi- Prolyl hydroxylases are dioxygenases dependent
um supplemented with 10% fetal-calf serum on Fe2+ and 2-oxoglutarate, and the H374 amino
seeded in 12-well plates (2×105 cells per well) 24 acid is one of the three critical residues that co-
hours before transfection. The transfection re- ordinate binding of Fe2+ ion (Fig. 3B).14
agent Lipofectamine 2000 (Invitrogen) was used Effects of the H374R mutation on PHD2 activ-
for transient transfections. The pcDNA3-HA- ity were evaluated by means of a reporter tran-
HIF-2α or HIF-1α vector (100 ng), pGL3 erythro- scription assay. HIF-α subunits (1α or 2α) were
poietin-promoter luciferase vector (200 ng), and coexpressed with a luciferase gene driven by hy-
pRenilla vector (20 ng) were cotransfected with a poxia-responsive elements from the erythropoietin

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 The n e w e ng l a n d j o u r na l
promoter gene. The addition of wild-type PHD2
caused the dose-related suppression of HIF-α–
mediated induction of the reporter gene, whereas
the response to the H374R PHD2 mutant was
impaired. On immunoblotting used to monitor
expression of the PHD2 protein, for equivalent
amounts of transfected plasmid, the wild-type
protein accumulated to a level that was higher than
that of the mutant protein, suggesting that the
mutant protein is unstable (Fig. 3C). To take this
effect into account, the amounts of transfected
plasmid were adjusted to yield equivalent amounts
of protein. With this adjustment, the impaired ac-
tivity of H374R mutant was confirmed — the ra-
tio of the activity of luciferase and that of renilla
for wild-type PHD2 was, on average, 2.5 times that
for mutant PHD2 (Fig. 3D, which shows the re-
sults obtained for HIF-2α; the same results were
observed for HIF-1α). This effect was not restricted
to erythropoietin-responsive elements, since it was
also obtained with the luciferase reporter gene
under the control of hypoxia-responsive elements
from the vascular endothelial growth factor pro-
moter (data not shown).
Discussion
The PHD2–VHL–HIF-2α pathway plays a crucial
role in erythropoiesis; a partial interruption of the
pathway can cause erythrocytosis, whereas dras-
tic alterations of the pathway are associated with
the development of tumors.11,15-17 Germ-line mu-
tations in the PHD2 gene have been reported in
patients with familial erythrocytosis, but not in
association with tumors.8-11 We describe here a
patient with a newly discovered PHD2 mutation
who first presented with isolated erythrocytosis
and subsequently was found to have a recurrent
paraganglioma. Tumor analysis showing loss of
heterozygosity involving the wild-type PHD2 sug-
gests that PHD2 can act as a tumor-suppressor
gene. Tumor-suppressor activity of PHD2 has re-
cently been incriminated in sporadic endometrial
cancer cells and cell lines.18,19 The oncogenic pro-
cesses induced by the loss of PHD2 are unknown
but could involve HIF-independent pathways, since
the H374 amino acid of the enzyme is part of a
highly conserved catalytic core that is present even
in prokaryotic pathogens that do not possess HIF.
Since the H374R mutant described here perturbs
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Copyright © 2008 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
Figure 3 (facing page). Description and Function
of the p.H374R PHD2 Mutant.
The H374 amino acid is conserved among human PHD
isoforms and also among homologous PHD isoforms in
other species (Panel A). Panel B shows the three-dimen-
sional structure of a PHD2 protein forming a complex
with Fe2+ and a 2-oxoglutarate competitive inhibitor (li-
gand). The image was produced with the use of the li-
gand 3D explorer software and is based on the 2g1m
crystal in the Protein Data Bank (www.wwpdb.org).14
Panel C shows immunoblot quantification of transfected
PHD2. Varying quantities of pcDNA3-HA-PHD2 expres-
sion vector (wild type or mutant) were transfected into
293T cells. Proteins were harvested 24 hours later and
were immunoblotted with anti-HA antibody. Panel D
shows the results of a functional study of PHD2 by
means of a reporter assay. Cells were cotransfected with
a fixed amount of pcDNA3-HIF-2α and various amounts
of pcDNA3-HA-PHD2 expression vectors, in addition to
pGL3 reporter vectors encoding luciferase under the
control of the hypoxia-responsive element of the eryth-
ropoietin gene and renilla, as a control for transfection
efficiency. Results are given in the percentage of the lu-
ciferase activity “reported” to renilla. The amount of
HA-PHD2 transfected was quantified through immuno-
blotting with anti-HA antibody.
the down-regulation of HIF by PHD2, and consid-
ering that paragangliomas are highly vascularized
tumors, alteration of the PHD2–HIF pathway could
contribute to the growth of a paraganglioma. Up
to 25% of paragangliomas are hereditary and are
mainly associated with germ-line mutations in the
SDHB, SDHD, and VHL genes or the proto-oncogene
RET.20,21 Our work suggests that PHD2 is a candi-
date gene involved in the development of paragan-
glioma and that mutation status should be explored
in families with unidentified genetic alterations
in the tumor.
From a clinical point of view, it is important to
point out that carriers of the heterozygous germ-
line PHD2 mutation who have been described in
the literature are younger than our patient was at
the time of diagnosis of paraganglioma (43 years
of age). One exception is a 54-year-old patient with
hypertension; this case could have been due to
catecholamine secretion from a misdiagnosed
paraganglioma.10 We recommend stringent follow-
up of carriers of the germ-line PHD2 mutation,
since their risk of a paraganglioma may be abnor-
mally elevated. In addition, preclinical models
with prolyl hydroxylase inhibitors to correct ane-
mia are currently being developed. The potential
 brief report

A
H374

Homo sapiens (PHD2) F W S D R R N P HE V Q P A Y A T

Homo sapiens (PHD1) F W S D R R N P HE V K P A Y A T
Homo sapiens (PHD3) F W S D R R N P HE V Q P A Y A T
Mus musculus (PHD2) F W S D R R N P HE V Q P A Y A T
Rattus norvegicus (PHD2) F W S D R R N P HE V Q P A Y A T
Drosophila melanogaster (fatiga A) F W S D I R N P HE V Q P A H R T
Caenorhabditis elegans (EglN9) F W S D R R N P HE V M P V F R H
Vibrio cholerae (SM20-related protein) F L S E – R F P HE V L E A H A D
Pseudomonas aeruginosa (PAO1) F M S A – G T E HE V L P A S R D

D315 H374

Fe2+ Fe2+
H313

Ligand
PHD2

C D
100

80
Luciferase Activity
(% of total)

Transfected 60
plasmid (ng): 50.0 25.0 12.5 5.0
Wild-Type HA- 40
WT-PHD2
Vector 20
Mutant HA-
H374R-PHD2 0
Vector HIF-2α: − + − + + + + − + + + +
0
0

PHD2 (ng):
.0
.0
.0
.5

5.
5.
.0
.0
.5
0
0

0
50
50
25
12

12
12
62
31
12
0.
0.

5.

Immunoblot
Anti-HA Antibody:
Wild-type HA-WT- Mutant HA-H374R-
PHD2 Vector PHD2 Vector

ICM
AUTHOR: Ladroue RETAKE 1st
oncogenic effect of this inhibition should be
REG F FIGURE: 3 of 3
No potential conflict of
2ndinterest relevant to this article was
reported. 3rd
evaluated before the approachCASE
is considered for We thank theRevised
patient and his family for their participation
therapeutic use.3,22 EMail Line
and Prof.4-C
Dominique Maïza, Prof. Nicole Casadevall, Prof. Pat-
SIZE
ARTIST: ts
Supported by grants from the French National
Enon Cancer Institute H/T H/T Dr. Brigitte
rick Bruneval, 33p9 Bressac de Paillerets, Dr. Anne-Paule
Combo
(Programme National d’Excellence Spécialisée Rein) and the Gimenez-Roqueplo, Dr. Ahyan Ulusakarya, Johny Bombled,
AUTHOR, PLEASE
French League against Cancer (Comités du Cher et de l’Indre). NOTE:
Caroline Chordi, and Prof. Gilbert Lenoir for their assistance.
Figure has been redrawn and type has been reset.
Please check carefully.

JOB: 35925 ISSUE: 12-18-08

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 brief report

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the HIF hydroxylase pathway. Mol Cell
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4. Ivan M, Haberberger T, Gervasi DC, et
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