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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1025-1031
Fusion of ETV6 to the Caudal-Related Homeobox Gene CDX2 in Acute
Myeloid Leukemia With the t(12;13)(p13;q12)
By
Andrew Chase,
Andreas Reiter,
Linda Burci,
Giovanni Cazzaniga,
Andrea Biondi,
Julie Pickard,
Irene A.G. Roberts,
John M. Goldman, and
Nicholas C.P. Cross
From the Department of Haematology, Imperial College School of
Medicine, Hammersmith Hospital, London, UK; and Clinica Pediatrica
Università di Milano, Ospedale San Gerardo, Monza, Italy.
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ABSTRACT |
The t(12;13)(p13;q12) is a rare, recurrent translocation reported in
a range of hematological malignancies. We have analyzed the molecular
basis of this lesion in three patients with acute myeloid leukemia
(AML), two of whom were known to have chromosome 12 breakpoints within
the ETV6 gene. Fluorescence in situ hybridization (FISH) with ETV6
cosmids indicated that this gene was also disrupted in the third
patient, while the normal ETV6 allele was retained. 3' rapid
amplification of cDNA ends (RACE) polymerase chain reaction (PCR) from
bone marrow mRNA of this individual identified a novel sequence fused
to ETV6 that was homologous to a region just upstream of the mouse CDX2
homeobox gene, the human homologue of which has previously been mapped
to chromosome 13q12. PCR primers designed to amplify an ETV6-CDX2
fusion identified two major transcripts from this patient. First, a
direct in-frame fusion between exon 2 of ETV6 and exon 2 of CDX2, and
second, a transcript that had an additional sequence of unknown origin
spliced between these same exons. Surprisingly, apparently normal CDX2
transcripts, usually expressed only in intestinal epithelium, were also
detectable in cDNA from this patient. Neither normal nor fusion CDX2
mRNA was detectable in the two other patients with a t(12;13),
indicating that this translocation is heterogeneous at the molecular
level. Reverse transcription-PCR analysis showed that CDX2 mRNA, but not ETV6-CDX2 mRNA, was strongly expressed in 1 of 10 patients with
chronic myeloid leukemia in transformation, suggesting that deregulation of this gene may be more widespread in leukemia. CDX2 is
known to regulate class I homeobox genes and its expression in
hematopoietic cells may critically alter the balance between differentiation and proliferation.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
TRANSLOCATIONS BETWEEN the long arm of
chromosome 13 and the short arm of chromosome 12 are rare nonrandom
abnormalities in acute lymphoblastic leukemia (ALL),1-3
acute myeloid leukemia (AML),4 secondary AML,5
myelodysplastic syndrome,6-8 and blast crisis of chronic
myeloid leukemia (CML-BC).9 The breakpoints are reported to
vary from 12p11 to p13 and from 13q11 to q14 but it is uncertain
whether this represents a true heterogeneity at the molecular level.
The region 13q12-14 is also the site of other abnormalities associated
with hematological malignancies, such as the
t(8;13)(p11;q12)10 or the interstitial deletions that are
often seen in patients with chronic lymphocytic leukemia or primary
myelofibrosis. Rearrangements of 12p (deletions and balanced or
unbalanced translocations) are common findings in diverse hematological malignancies. In many cases these rearrangements target ETV6 (initially called TEL), a gene at 12p13 that has been reported to form fusions with multiple partners: PDGFRB,11 MN1,12
ABL,13 CBFA2 (AML1),14 MDS1/EVI1,15
STL,16 and JAK2.17 In many cases the normal ETV6 allele is deleted in patients with these abnormalities.
Here we describe a novel fusion between ETV6 and CDX2 at 13q12 in a
patient with AML and a t(12;13). In addition, aberrant expression of
CDX2 was found in a case of CML-BC who did not have any cytogenetically
visible abnormality of chromosome 13. CDX2 is a homeobox gene related
to the Drosophila gene caudal and is not normally expressed in
hematopoietic cells. Although mutations of CDX2 may be associated with
rare cases of colorectal cancer,18 abnormalities of this
gene have not been described previously in leukemia. It is becoming
increasingly clear that homeobox genes are involved in the processes of
normal hematopoietic cell proliferation and differentiation, and that
disruption of their normal patterns of expression can lead to leukemia.
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MATERIALS AND METHODS |
Case report and patient material.
A 66-year-old man presented with a short history of palpable lymph
nodes in both axillae and easy bruising for the previous 2 weeks.
Laboratory findings showed a leukocyte count of 144 × 109/L with 98% blasts, platelet count of 23 × 109/L, and a hemoglobin level of 10.2 g/dL. A bone marrow
(BM) biopsy showed virtually all cells to be myeloblasts with
occasional Auer rods and little differentiation; cytogenetic analysis
demonstrated a translocation t(12;13)(p13;q12). A diagnosis of AML M1
was made. The patient achieved complete remission after three courses
of chemotherapy. However, 38 months later he relapsed with a leukocyte count of 134 × 109/L, platelet count of 51 × 109/L, and a hemoglobin level of 12.4 g/dL. Cytogenetic
analysis showed a deletion of 6q in addition to the t(12;13).
Chemotherapy was initiated and BM examination showed less than 5%
blasts after completing the second course. Unfortunately, fever
occurred during neutropenia and a pneumonia was diagnosed. The patient
developed generalized sepsis despite antibiotic treatment and died 2 months after the diagnosis of relapse.
For this patient (patient no. 1), peripheral blood and BM cells that
had been cryopreserved at relapse were available for analysis. We also
analyzed cDNA from two other t(12;13) patients (patients nos. 2 and 3)
with AML M0 who have been described previously.4
As controls, peripheral blood (PB) or BM was obtained from 10 patients
with AML, 10 patients with myeloid blast crisis of CML, and 5 normal individuals.
Fluorescence in situ hybridization (FISH).
Cytogenetic cell suspension was not available for patient no. 1 and
cryopreserved cells failed to grow in culture. Therefore, for FISH
analysis we used cytospin preparations of interphase nuclei prepared
from cryopreserved cells which were fixed and stored at  20°C in
3:1 methanol/acetic acid until required. The cosmids 179A6 and 148B6
(kindly provided by Dr P. Marynen, Leuven, Belgium), which
contain ETV6 exons 1 and 8, respectively, were labeled with biotin and
digoxigenin by nick-translation and detected with rhodamine and FITC,
respectively. CDX2 cosmids ICRFc108G2043QD2 and ICRFc108B0629QD2 were
labeled with digoxigenin. FISH was performed according to standard
procedures.19 Images were captured using a
Vanox fluorescence microscope (Olympus Optical Co, Ltd,
Tokyo, Japan) equipped with a CCD camera and SmartCapture software
(Digital Scientific, Cambridge, UK).
Rapid amplification of cDNA ends (RACE) polymerase chain reaction
(PCR).
RNA was extracted from cryopreserved cells using an RNeasy Mini Kit
(Qiagen, Hilden, Germany). For the 3' RACE, the primer Ro-Ri-dT17 was used for reverse
transcription
(5'-AAGGATCCGTCGACATCGACAATCCTA-CGACTCACTATAGGGATTTTTTTTTTTTTTTTT-3'), an oligo-dT sequence joined to a "double adapter" sequence that allows a two-step RACE amplification.20 RACE PCR was
performed using the nested ETV6 exon 2 primers TF
(5'-CAGGAACGAATTTCATATACACCT-3') and TG (5'-CCAGTGCCGAGTTACGCTTCCT-3')
and outer and inner adapters Ro
(5'-AAGGATCCGTCGACATCGAT-3') and Ri
(5'-GACATCGATCCTACGACTCA-3'). Amplified products were cloned using a TA
Cloning Kit (Invitrogen, Leek, The Netherlands). Clones that were
positive for an internal ETV6 exon 2 probe were sequenced. For the 5'
RACE, reverse transcription (RT) was performed using the ETV6 exon 3 primer 5RA (5'-TTTGCCATTCATTTCAAA-3'). The 5' cDNA ends were poly-A
tailed, first-step PCR was performed with
Ro-Ri-dT17, Ro and 5RB
(5'-GTGTTGCTGTCAATTGGCCT-3'), and second step with Ri and
5RC (5'-GAAAACTCATTTTCAGCCCAC-3'). Products were cloned as above and
those that were positive for an internal ETV6 exon 3 probe but negative
for an ETV6 exon 2 probe were sequenced. The position of all primers
used is shown in Fig 4.
RT-PCR.
Patient RNA was extracted and reverse transcribed with random hexamer
primers. Quality of cDNA was confirmed in all cases by amplification of
the normal ABL gene.21 All amplifications were performed
for 32 cycles with an annealing temperature of 60°C to 66°C.
DNA sequencing and analysis.
Clones and PCR products were directly sequenced by thermal cycling with
fluorescent dye terminators. Reactions were analyzed on an automated
sequencer (model ABI 373A; Applied Biosystems, Foster City, CA).
Physical mapping.
CDX2 cosmids were isolated by screening a gridded chromosome 13 specific library, obtained from the Ressourcen Zentrum Primär Datenbank (RZPD; Berlin, Germany). CDX2 positive yeast artificial chromosomes (YACs) were identified by screening a panel of clones that
were known to map to 13q12-14 (obtained from the UK HGMP Resource
Centre, Hinxton, UK).
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RESULTS |
FISH.
FISH was used to show the involvement of ETV6 in patient no. 1. In
normal nuclei, FISH with cosmids for ETV6 exons 1 and 8 shows two
fusion signals indicating two intact ETV6 genes. Patient material
showed one fusion signal and single, separate red and green signals,
indicating a breakpoint in one ETV6 allele and that the normal allele
is not grossly deleted (Fig 1A). However, this result does not exclude the possibility of a small intragenic deletion or other mutation that may have inactivated the normal copy of
ETV6.
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| Fig 1.
(A) FISH analysis of two nuclei from patient no. 1 with
cosmids 179A6 (detected with rhodamine) and 148B6 (detected with FITC),
which hybridize to ETV6 exons 1 and 8, respectively. Colocalized
signals indicate the normal ETV6 allele, while separate red and green
signals indicate a break within ETV6. (B) Three nuclei from patient no.
1 hybridized with cosmids 179A6 (detected with rhodamine) and
ICRFc108G2043QD2 (CDX2 exon 1 plus upstream sequence, detected with
FITC). Colocalization of these cosmids indicates a chromosome 13 break
upstream of CDX2 exon 1.
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RACE PCR.
Because the FISH results had indicated a break between ETV6 exons 1 and
8, 3' RACE PCR using primers designed to ETV6 exon 1 was performed to
capture any novel sequence that may have become fused to ETV6. 3' RACE
PCR resulted in 11 ETV6+ clones. Of these, 10 contained
ETV6 sequence only and one, clone 3R30, contained 547 bp of
novel sequence immediately after ETV6 exon 2 (Fig
2A). A BLAST search showed that part of
this sequence was homologous to a region shortly upstream of the mouse
Cdx2 gene (Genbank accession no. U00454, bases 475-541). The human homologue, CDX2 (originally referred to as CDX3), has been
cloned22 and mapped to 13q12 by FISH.23
Therefore, it was likely that CDX2 was the partner gene. 5' RACE PCR
from ETV6 exon 3 failed to find any novel sequences.
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| Fig 2.
(A) DNA sequence of clone 3R30. The end of ETV6 exon 2 shown in capitals and the sequence with partial homology to a region
upstream of the mouse CDX2 gene is underlined. (B) Amino acid and mRNA
sequences of normal ETV6, normal CDX2 and the smaller ETV6-CDX2 product
at the site of fusion. (C) Sequence of larger ETV6-CDX2 fragment. The
end of ETV6 exon 2 and the start of CDX2 exon 2 are shown in capitals.
The stop (TAA) and potential start (ATG) codons referred to in the text
are shown underlined.
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RT-PCR and sequence analysis.
Primers designed to detect an ETV6-CDX2 fusion, TG (ETV6 exon 2) and R4
(CDX2 exon 2, 5'-AGTGAAACTCCTTCTCCAGGTC-3') resulted in the
amplification of two major and several weaker bands from cDNA derived
from both PB and BM leukocytes of patient no. 1 (Fig 3A). No amplification products were
obtained from cDNAs made from patient nos. 2 and 3, from normal BM or
normal PB (Fig 3A). Amplification of the normal ABL gene from these
samples indicated that the quality of the cDNA was good (not shown).
Sequencing showed that the smaller of the two major bands from patient
no. 1 was a direct in-frame fusion between exon 2 of ETV6 and exon 2 of
CDX2 (Fig 2B). The larger band had an additional sequence inserted
between these same exons (Fig 2C), which was related to the novel
sequence identified by 3' RACE PCR. Two of the weakly amplified bands
were also sequenced. Both were identical to the large major transcript
except for the addition of 97 bp of ETV6 intron 2 sequence in one case
and the deletion of the first 83 bp of the inserted sequence in the
second. No amplification products were obtained from any individual
using primers to CDX2 exon 1 and ETV6 exon 3, indicating that the
reciprocal CDX2-ETV6 fusion is not expressed (not shown).
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| Fig 3.
RT-PCR analysis from patient and control cDNAs. (A)
ETV6-CDX2 (primers TG and R4) from patients 1, 2, and 3, normal BM and
PB leukocytes. (B) CDX2 (primers R6 and R4) from the same patients and
(C) CDX2 and ABL from 10 patients with myeloid blast crisis of CML
(lanes 1 through 10) or AML (lanes 11 through 20).
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Using primers (R6, 5'-ATGTACGTGAGCTACCTCCTGG-3', and R4) to CDX2 exons
1 and 2 (Fig 4), we confirmed that
transcripts of this gene are undetectable in normal PB and BM
leukocytes. CDX2 mRNA was also undetectable in patients no. 2 and 3. Surprisingly, however, in view of the fusion sequences described above,
a strong amplification product was obtained from patient no. 1 (Fig
3B). The identity of this product was confirmed by sequencing. This
finding shows that, in addition to the ETV6-CDX2 fusion, patient no. 1 expresses CDX2 transcripts that are predicted to be translated into
normal, full-length CDX2 protein.
To determine if CDX2 is expressed in other patients with leukemia, we
screened 20 patients who did not have cytogenetic evidence of
chromosome 13 abnormalities by RT-PCR with primers R6 and R4. Surprisingly, CDX2 mRNA was detected in one patient with CML-BC (Fig
3C). Further RT-PCR with various combinations of CDX2 and ETV6 primers
failed to identify an ETV6-CDX2 fusion in this patient (not shown).
Physical mapping.
Screening of a 13q YAC panel by PCR with primers R4 and R6, which
amplify the first two exons and a short intron, identified the CEPH YAC
272G3 to be positive for CDX2. The 540-kb YAC 272G3 has been partially
mapped and shown to contain the FLT1 and FLT3 genes.24
The fact that the 3' RACE PCR product and the larger ETV6-CDX2 fusion
transcript contained a sequence that matched a region shortly upstream
of the mouse Cdx2 gene strongly suggested that the chromosome 13 breakpoint must lie upstream of the human CDX2 gene. This hypothesis is
supported by the fact that no reciprocal CDX2-ETV6 transcripts were
detected. To confirm the position of the breakpoint, two chromosome 13 cosmids containing the region immediately upstream of human CDX2 were
isolated by screening a library with the inserted sequence from the
larger fusion transcript. PCR analysis showed that clone
ICRFc108G2043QD2 also contained CDX2 exon 1 and that clone
ICRFc108B0629QD2 contained upstream sequence only. Both cosmids
hybridized to chromosome 13q12 only in normal control metaphases.
Two-color FISH analysis on nuclei from patient no. 1 showed
colocalization of both these cosmids with the ETV6 exon 1 cosmid (Fig
1B), thus confirming that the break is upstream of CDX2 exon 1.
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DISCUSSION |
We have found a fusion between ETV6 and a new partner gene, CDX2, in a
patient with AML M1 with a t(12;13)(p13;q12). Chimeric ETV6-CDX2 fusion
transcripts were not detected in two other patients with AML M0 and a
t(12;13) who have been shown previously to have breakpoints within the
ETV6 gene,25 indicating that this translocation is
heterogeneous at the molecular level. Several different types of
chimeric mRNA were identified in patient no. 1, of which two were
predominant. The first of these was a direct in-frame fusion between
ETV6 exon 2 and CDX2 exon 2 and is predicted to encode a 187-amino acid
fusion protein consisting of a short ETV6-derived amino-terminal domain
of unknown function joined to the DNA-binding domain of CDX2. This
protein would lack the ETV6 helix-loop-helix domain, implicated in the
leukemogenic activity of the fusions between ETV6 and ABL, PDGFRB, and
JAK2,26-28 and also the ETV6 DNA-binding domain. The second
major transcript had an additional 547 bp spliced between ETV6 exon 2 and CDX2 exon 2. This transcript would not be translated into a fusion
protein because the additional sequence introduces an in-frame stop
codon 57 bp after the end of ETV6 exon 2. Potentially it could encode a
74-amino acid truncated ETV6 protein. In addition, there are two
possible AUG start codons within the inserted sequence that are in
frame with CDX2 and it is conceivable that these could initiate
translation, for example via an internal ribosome entry site (IRES), a
mechanism of internal ribosome binding found in some viruses and
several cellular genes.29
Unexpectedly, we also detected apparently normal CDX2 transcripts in
patient no. 1 using primers designed to amplify between CDX2 exons 1 and 2. In adults, expression of this gene is usually tightly restricted
to the intestinal epithelium.30 However, analysis of a
further 20 patients with acute leukemia showed similar transcripts in
one other case, indicating that ectopic expression of CDX2 is not
restricted to patients with a t(12;13) or other abnormalities of
chromosome 13. Taken together, these data suggest that the leukemogenic
event in patient no. 1 may have been the ectopic expression of CDX2,
and that deregulation of this gene by a mechanism that remains to be
defined may be a contributory factor in other leukemias. This situation
is reminiscent of the EVI-1 gene: overexpression of EVI-1 was initially
found in association with the t(3;3)(q21;q26) or the inv(3)(q21q26).
Subsequently, however, EVI-1 overexpression was found in other cases of
acute leukemia.31 Furthermore, a related translocation, the
t(3;12)(q26;p13), has been described in which a fusion was found
between ETV6 exon 2 and MDS1 exon 2, which in turn was fused to
EVI1.15 The investigators suggested that the function of
ETV6 in these cases was to drive the inappropriate expression of
MDS1/EVI1.
We have shown that the chromosome 13 breakpoint lies upstream of the
CDX2 gene. One possible explanation for the aberrant expression of
apparently normal CDX2 transcripts could be that this gene is
translocated downstream of one of the two alternative first ETV6
promoters that are located between ETV6 exons 2 and 3,15,32
and that this promoter then drives the expression of a CDX2 mRNA that
would be predicted to be translated into normal CDX2 protein (Fig
5, transcript a). The fusion transcripts
would be initiated at the normal ETV6 promoter, from which CDX2 exon 1 would be spliced out due to the lack of a 3' splice acceptor sequence,
resulting in the observed ETV6 exon 2-CDX2 exon 2 chimeric mRNAs or
various minor products (Fig 5, transcripts b and c). However,
alternative explanations for the ectopic expression of CDX2 are
possible. The ETV6-CDX2 fusion protein may dysregulate the normal
and/or the translocated CDX2 allele. Alternatively, translocation of CDX2 and its promoter into the active ETV6 locus may
relieve chromatin-mediated transcriptional suppression of CDX2.
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| Fig 5.
Schematic diagram to illustrate a possible mechanism for
expression of an apparently normal full-length CDX2 transcript (a) and
ETV6-CDX2 fusion transcripts (b and c). ( , exon;  , promoter;  ,
breakpoint).
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CDX1 and CDX2 in humans, Cdx1, Cdx2, and Cdx4 in mice, and also genes
identified in chicken, Xenopus, zebra fish, silk worm, and
Caenorhabditis elegans are related to the Drosophila
homeobox gene caudal. Caudal family members share a highly
conserved DNA-binding homeodomain that is similar to, but distinct
from, the homeodomains of the class I homeobox genes. The caudal
protein forms an anterior-posterior gradient in the Drosophila
oocyte, which plays an important role in embryo
segmentation.33 Later in embryogenesis caudal is involved in formation of the gut, Malpighian tubules, and other posterior structures. Similarly in mice, in early embryogenesis Cdx2 is expressed
in posterior regions, but in later embryos and adults Cdx2 is reported
as restricted to the intestinal epithelium.22,30,34 In
Drosophila, mutations of caudal produce severe disruptions to
body segmentation.35 In mice, Cdx2 homozygous null mutants are not viable beyond 3 to 5 days postcoitum, but heterozygotes show an
anterior homeotic shift of the vertebrae. Surprisingly, these mice
developed intestinal neoplasia and metaplasia, suggesting that
abnormalities of CDX2 may be relevant to human intestinal malignancies.36 Indeed, a case of colorectal cancer
with biallelic mutations of CDX2 has recently been
described.18 The fundamental segment disruption in
caudal-null Drosophila and the homeotic changes in Cdx2
heterozygous mice suggest that CDX2 influences the expression of other
homeobox genes and its action may be one of the early steps in the
hierarchy of control of homeobox gene expression. In support of this
hypothesis, CDX2 consensus DNA binding sequences have been identified
in the promoter regions of 13 murine homeobox genes37 and 6 human homeobox genes.36,38
Disruption or aberrant regulation of homeobox gene have been implicated
in the pathogenesis of distinct leukemias. HOXA9 is fused to the
nucleoporin gene NUP98 by the t(7;11) in AML.39,40 HOX11 is
juxtaposed to the T-cell receptor by the t(10;14) in T-ALL41 and PBX1 is fused to E2A by the t(1;19) in pre-B
ALL. The MLL gene, involved in translocations with many different
partners in both lymphoblastic and myeloblastic leukemias, is a human
homologue of the Drosophila gene trithorax, a positive
regulator of homeobox gene expression. In addition, CBFA2 and CBFB,
which are disrupted by the t(8;21) and inv(16), respectively, in AML,
contain domains homologous to runt, a Drosophila pair-rule gene
involved in defining expression domains of the Drosophila class
I homeobox genes. Finally, retinoic acid is a potent modulator of
homeobox gene expression42 and this may be
relevant to the mechanism of transformation in AML induced by the
fusion between PML and the  -subunit of the retinoic acid receptor in
the t(15;17). Our findings provide a further example of a deregulated
homeobox gene in leukemia and reinforce the notion that alterations in
the expression patterns of this family may critically alter the balance
between hematopoietic cell differentiation and proliferation.
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ACKNOWLEDGMENT |
We thank the MRC HGMP Resource Centre (Hinxton, UK) and the RZPD
(Berlin, Germany) for providing the YAC and cosmid clones used in this
study, and also Dr P. Marynen (Leuven, Belgium) for providing the ETV6
cosmid clones.
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FOOTNOTES |
Submitted February 28, 1998; accepted September 25, 1998.
Supported by the Leukaemia Research Fund, the Dr. Mildred Scheel
Stiftung, the Associazione Italiana per la Ricerca sul Cancro, and the
Fondazione Tettamanti.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Andrew Chase, Department of
Haematology, Imperial College School of Medicine, Hammersmith
Hospital, Du Cane Rd, London W12 ONN, UK; e-mail: achase{at}rpms.ac.uk.
| |
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Abstract
Introduction