Amplification of band q22 of chromosome 21, including AML1, in older children with acute lymphoblastic leukemia: An emerging molecular cytogenetic subgroup

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representative of MM patients. Bone marrow mononuclear cells
were isolated by Ficoll–Hypaque sedimentation and extracted DNA
was modified for MSP by bisulfite using the CpGenome
TM
DNA
Modification Kit (Intergen, Purchase, USA). SOCS-1 gene promoter
regions were amplified with DNA methylated and unmethylated
specific primers as previously described.
5
A total of 51 samples of MM bone marrow cells were analyzed by
MSP. Selective methylation of SOCS-1 gene was found in 38/51
patients (74.5%). No correlation could be made between SOCS-1
gene methylation and gender, age, isotype, level of M-compo-
nent, stage of the disease, serum levels of albumin, creatinin,
calcium, b2-microglobulin, LDH, C-reactive protein, or response
to treatment. Overall survival was not significantly different
between patients with methylated and unmethylated SOCS-1 gene
(P¼0.58), median survival being estimated at 27.1 months (95% CI,
14.4–39.8) and 23.1 months (95% CI, 17.3–28.9), respectively
(Figure 1).
Methylation of SOCS-1 gene is frequent in MM, occurring at
frequencies of 75% in our series. It may represent an important
epigenetic event in the pathogenesis of MM. However, SOCS-1
gene methylation does not seem to influence the clinical outcome of
MM patients.
S Depil
1,2
A Saudemont
1,2
B Quesnel
1,2
1
Unite
´INSERM 524, IRCL, Lille, France;
2
Service des Maladies du Sang, CHU de Lille,
Lille, France
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Amplification of band q22 of chromosome 21, including AML1, in older children with
acute lymphoblastic leukemia: an emerging molecular cytogenetic subgroup
Leukemia (2003) 17, 1679–1682. doi:10.1038/sj.leu.2403000
TO THE EDITOR
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease at
the chromosomal and molecular levels. Several subgroups of
chromosomal abnormalities have been identified in pediatric B-cell
precursor ALL: hyperdiploidy in which more than 50 chromosomes
are present, near haploidy, and translocations t(12;21), t(1;19),
t(9;22), and t(4;11) or other 11q23 abnormalities. With the
development of specific fluorescence in situ hybridization (FISH)
probes to evaluate metaphase chromosomes or interphase nuclei,
chromosomal abnormalities can now be detected when leukemic
cells have cryptic alterations or a karyotype that cannot be
determined. The frequent use of TEL-AML1 probes to evaluate the
cryptic t(12;21) have identified isolated cases in which the AML1
gene is amplified or over-represented.
1–5
This chromosomal
abnormality is most often detected by conventional cytogenetic
methods as a tandem duplication of chromosome band 21q22 or as
marker chromosomes of unknown origin.
1-5
However, in B-cell
precursor ALL, various numerical and structural abnormalities of
chromosome 21 can lead to multiple copies of AML1. Among the
abnormalities are trisomy or tetrasomy 21 (which can be the sole
abnormality or associated with high hyperdiploidy 450 chromo-
somes), and isochromosomes 21q or ider(21q)t(12;21). Therefore,
more stringent molecular methods of detection are needed to
specifically identify AML1 amplification.
Before we attempted to confirm that amplification of band 21q22,
including AML1, is characteristic of an emerging ALL subtype, we
developed a FISH-based inclusion criteria for detection of AML1
amplification/over-representation by FISH. These consisted of
detection of four or more AML1 signals in interphase nuclei, and
the colocalization of three or more signals on the same metaphase
chromosome; when no mitotic cells were obtained, the presence of
an AML1 amplification was considered to have occurred if FISH
resulted in five or more AML1 signals in interphase nuclei. It is
generally accepted that up to four to five copies of a gene the term of
over-representation should be prefered, and above that number
amplification can be used. On the basis of these inclusion criteria,
we report here 16 pediatric patients with B-cell precursor ALL and
amplification/over-representation of band q22 including AML1
(Table 1).
Patients were referred to pediatric centers in France (Centre
Hospitalier Universitaire CHU Brest; CHU Nantes; CHU Nice,
France; CHU Saint-Louis, Paris, France), St Jude Children’s Research
Hospital (Memphis, TN, USA), Mount Sinai Medical Center (New
York, NY, USA), or Chaim Sheba Medical Center (Tel-Hashomer,
Israel). The diagnosis of B-cell precursor ALL was based on the
morphology criteria of the French–American–British Group, the
expression of B-cell-associated antigens CD19, CD22, CD10, and
the absence of membrane immunoglobulins. Cytogenetic analyses
were performed on mitotic bone marrow or blood cells according to
standard procedures. Chromosomes were trypsin-Wright or RHG
banded. Karyotyping was carried out according to the guidelines of
the International System for Human Cytogenetic Nomenclature
(ISCN 1995). Patients were enrolled in one of the following front-
line clinical trials: protocols FRALLE 1993 and 2000, EORTC 58981,
St Jude protocols Total XII and XIII, and Berlin–Frankfurt–Munster
(BFM) protocols 1995 and 1998. The studies were approved by the
appropriate ethic committees of each institution, and informed
consent was obtained from patients or guardians.
In five of the seven cytogenetic laboratories involved in this study,
the detection by FISH of the t(12;21) was performed prospectively
for the last 2 years on all newly diagnosed B-cell ALL cases. In the
remaining two centers, FISH using a probe specific to the TEL-AML1
fusion gene is usually performed to confirm positive PCR results, or
when chromosome 12p or chromosome 21 abnormalities are
suspected.
The LSI TEL-AML1 ES dual-color translocation probe (Vysis,
Downer’s Grove, IL, USA and Adgenix, Voisin-Le-Bretonneux,
France) was used by all laboratories. This probe is a mixture of the
Received 14 January 2003; accepted 28 March 2003
Correspondence: Dr SD Raynaud, Unite
´de Cytoge
´ne
´tique des
He
´mopathies Malignes, Ho
ˆpital de l’Archet, BP79, Nice Cedex
06202, France; Fax: +33 4 920 364 65
Correspondence
1679
Leukemia

LSI TEL probe labeled with Spectrum Green and the AML1 probe
labeled with Spectrum Orange. The approximately 500 kb AML1
probe spans the entire AML1 gene and contains genomic DNA
centromeric to this gene, which is located at 21q22. The probe was
used according to the manufacturer’s recommendations. Briefly,
slides were denatured at 751C for 2 min; probes were denatured at
the same temperature for 5 minutes. Subsequently, the two were
hybridized overnight at 371C. Hybridization signals were evaluated
by using DAPI/FITC/rhodamine triple-band pass filter sets.
According to our FISH inclusion criteria, we found that the
leukemic cells from the 16 pediatric patients with newly diagnosed
B-cell precursor ALL had multiple copies of band q22 including
AML1. The AML1 copy number ranged from four to more than 10
per interphase nuclei or metaphase chromosomes (Table 1 and
Figure 1). Multiple 21q22 and AML1 signals were clustered in an
area within the interphase nuclei in most cases (Figure 1, panels A–
C), and were consistently located on the same metaphase
chromosome. All cases in this study had high percentages of cells
with the AML1 amplification; in fact, almost all of the leukemic cells
contained this amplification, a finding consistent with the hypoth-
esis that this is a major oncogenic event. Two signals specific for the
TEL probe were observed in all cases.
When conventional cytogenetic findings were evaluated, we
identified four ploidy patterns (Table 1): pseudodiploid (n¼8), low
hyperdiploid (from 47 to p50 chromosomes) (n¼3), high
hyperdiploid 450 chromosomes (n¼2), and diploid (n¼1). No
karyotype was determined for two additional cases because of the
absence of mitotic cells; no DNA index was available for these
patients. All patients in the pseudodiploid and low hyperdiploid
groups had marker chromosomes, numerical or structural abnorm-
alities of chromosome 21 such as add(21q), del(21q), trp(21q),
qdq(21q), or both marker chromosomes and chromosome 21
abnormalities. FISH with whole-chromosome painting probes
showed that these marker chromosomes originated from chromo-
some 21 (data not shown). FISH using the locus-specific AML1
probe resulted in the appearance of several signals on a single
chromosome (Figure 1, panel d). Conventional cytogenetics
revealed various structural or numerical chromosome abnormalities
Table 1 Pediatric B-cell precursor ALL cases with AML1 amplification (present study and published cases)
Study
(references)
Case No Sex/Age WBC 10
9
/l
(blast %)
Karyotypes AML1 signals by FISH
(% of abnormal IN)
Follow-up CR
Pseudodiploid
PS 1 F/11 18 (60) 46,XX,del(8)(q?),+13,-19,add(21)(p) [5] >10 (60) 20m
+
PS 2 F/13 2.8 (50) 46,XX,-21,+mar [9] /46,XX [2] 5–10 (92) 18m
+
PS/(4) 3* M/17 1.0 (50) 46,XY,add(1)(q25),add(21)(q21) [6] /46,XY [14] 8 (98) 19m
+
PS/(4) 4* F/19 10.1 (72) 46,XX,del(7)(p14p21),-21,+mar [10] /46,XX [2] 6–8 (99) 21m
+
PS 5 M/14 2.2 (22) 46,XY,inv(7)(p?15q?21),-21,+mar [2] /46,XY [4] 5–7 (72) 23m, 2m
+
PS 6 M/12 15.1 (70) 46,XY,-21,+mar [8] 5–7 (98) 2m
+
PS 7 F/13 3.8 (1) 46,XX,del(7)(q22q35),del(11)(p12),add(21)(p11.2)
[9] /46,XX [5]
5 (96.5) 61, 56, 10m
+
PS 8 F/15 9.9 (64) 46,XX,trp(21)(q11.2q22) [13] /46,XX [7] 4 (68) 86m
+
(1) #1 M/12 4.3 (NA) 46,XY,del(18)(p11),der(21) 10–15 NA
(2) #3 F/11 NA 46,XX,-21,+mar 564m
(2) #1 M/15 4.3 (35) 46,X,-Y,add(21)(q22),+mar1 [8] /46,XY [12] 4–5 32m
+
(3) #1 F/10 1.4 (4) 46,XX,der(21) [2] 4–5 14m+
(7) #40 F/15 NA 46,XX,add(1)(p?),del(6)(q25) >4 13m
+
(8) #44 M/13 7.6 (NA) 46,XY,i(9)(q10),-16,+mar (trp 21q using SKY) 4 18m
+
Low hyperdiploid
PS/(5) 9* F/8 0.9 (1.5) 47,XX,+X,del(21)(q22),der(21) [12] /46,XX [4] 510 (85) 9m
+
PS/(10) 10* F/12 7.1 (3) 48,XX,+X,+10,del(11)(q23),qdp(21)(q11q22)
[13] /46,XX [7]
5 (66) 48m+
PS 11 F/13 6.6 (55) 47,XX,?add(4)(q31),del(7)(q3?2),i(21),+mar
[5] /46,XX [10]
5 (37) 10m
+
(3) #2 M/11 5.9 (0) 47,X,+X,inv(Y)(p11.2q12),+10,-20,der(21) [20] 6 7m
+
(1) #2 F/5.6 26.3 (NA) 48,XX,-20,+der(21),+2mar 6 NA
High hyperdiploid >50 chromosomes
PS 12 M/5 7.2 (NA) 56,XY,+X,+Y,+6,+10,+14,+17,-19,+21,
+22,+mar1,+mar2, +mar3 [5] /46,XY [18]
5–10 (30) 24m
+
PS 13 F/6 3,1 (12) 54,XX,+X,+6,+9,+14,+17,+18,+2mar [12] 4–10 (93) 5m+
(2) #2 M/6 4.9 (61) 53,XY,+X,+Y,inv(3),add(4),+9,+17,+21,+21,
+add(21)(q22)
4–5 Na
Normal karyotype
PS 14 M/11 NA 46,XY [30] 3–10 (NA) NA
(9) #1 F/15 NA 46,XX [20] 15–20 (70) Relapse
(8) #64 M/14 14.5 (NA) 46,XY 6–15 48m
+
(7) #38 M/2.9 NA 46,XY 4–5 14m
+
(7) #39 F /3.4 NA 46,XY >4 8m
+
Karyotype failure
PS 15 F/11 1.6 (4) Failure >10 (97) 75m
+
PS 16 M/7 NA Failure 4–10 (NA) NA
(8) #65 F/8 2.0 (NA) Failure 6–15 52m+
Notes: PS, cases from the present study; *, cases partially described in Penther et al,
4
Morel et al
5
and Mathew et al;
10
IN, interphase nuclei CR m+, months of ongoing
complete remission; NA, not available. The chromosomes that most likely hybridized with AML1 probe were written in bold.
Correspondence
1680
Leukemia

were also present in most cases. Among the patients in the high
hyperdiploidy group, at least two did not have tetrasomy 21 as
indicated by conventional cytogenetics. This finding suggests
that the 21q22 amplification could be a functional equivalent of
tetrasomy 21 in high hyperdiploid ALL. Moreover, the marker
chromosome in which AML1 was amplified was duplicated in
patient 13 (Figure 1, panel b). However, caution should be taken in
this interpretation as possible asymmetry of replication and the
presence of twin/double spots cannot be ruled out in some of these
cases. The interpretation of cases with normal karyotypes and 21q22
amplification is equivocal; probably the leukemic cells are not
dividing; alternatively the amplification could be cryptic. In all
cases, conventional cytogenetics, FISH and/or molecular analyses
did not detect recurrent translocations, including the t(12;21),
t(9;22), and t(4;11), in association with AML1 amplification.
When the major clinical and biological features of the pediatric
patients with ALL and multiple copies of 21q22 including AML1
were analyzed, particular features appeared to be associated with
the pseudodiploid and low hyperdiploid groups. Within these
groups (n¼11), the median age was 13 years (range, 8–19); in
contrast, the two patients in the high hyperdiploid group were only
5 and 6 years old. The peripheral white blood cells (WBCs) counts at
diagnosis were low (median, 6.6 10
3
/ml; range, 0.9–18). In
comparison, the median age of patients with B-cell precursor ALL
in the FRALLE 93 trial (n¼1195) was 4.7 years (range, 0.1 to 19
years) and the median WBC count was 9.5 10
3
/ml (range, 0.3–
1350).
6
Immunological analysis using a standard antibody panel
revealed common CD10-positive B-cell precursor phenotype in all
cases. Furthermore, six cases were early pre-B (Cm

, sIgm

), five
were pre-B (Cm
+
, sIgm

) and one was transitional (Cm
+
, sIgm
+
). Some
genetically distinct subgroups of precursor-B ALL are closely
associated with characteristic but not unique immunophenotypes.
For example, t(1;19) with CD19
+
/CD10
+
/CD34

, pre-B ALL
phenotype; t(12;21) with CD19
+
/CD10
+
/CD9
dim
/CD20
dim
and
either CD13
+
or CD33
+
; and t(4;11)(q21;q23) with CD19
+
/CD10
-
/
CD15
+
. We observed no particular association of 21q22 amplifica-
tion with immunophenotype. Remission was achieved in the 14
patients for whom clinical records were available. The median
follow-up period was 21 months (range, 0.5 to 127). Although two
of the patients relapsed, one is in second remission, and the other is
in third remission.
Using our FISH criteria, we evaluated cases from the literature
and identified 14 additional pediatric cases with ALL and
amplification or over-representation of 21q22, including eight cases
with pseudodiploidy or low hyperdiploidy. The clinical and
biological features of these eight patients were consistent with our
findings, including older age (median, 11.5 years) and low WBC
counts (median, 4.3 10
3
/ml) (Table 1).
The similarity in the characteristics of these cases suggests that
amplification of 21q22, including AML1, within pseudodiploid or
low hyperdiploid leukemic cells represents an emerging subtype of
B-cell precursor ALL, potentially distinct from the subtypes
characterized by the t(12;21) and other recurrent chromosome
abnormalities. A systematic prospective screening of AML1 ampli-
fication in ongoing ALL clinical trials is now necessary to determine
the frequency and the prognostic value of this cytogenetic
abnormality.
It is unknown what genes are the targets of the amplification
process. Besides AML1 there is evidence that 21q22.13-22.2 and
subtelomeric 21q band are also amplified (V Najfeld, data not
shown), and other gene(s) at 21q22 might be oncogenic target(s)
activated by amplification. Genomic and expression analyses
should help to elucidate the oncogenic mechanisms associated
with multiple copies of 21q22 and AML1 amplification in this newly
recognized molecular cytogenetic subgroup of ALL.
Acknowledgements
This study was supported in part by grants from the National
Institutes of Health (CA 21765), the American Lebanese Syrian
Associated Charities, and the French Department of Health
(Programme de Soutien aux Innovations Diagnostiques et The
´r-
apeutiques Couˆteuses). We thank Dr JC Jones (St Jude Children’s
Research Hospital) for critical reading of the paper.
J Soulier
1
L Trakhtenbrot
2
V Najfeld
3
JM Lipton
3
S Mathew
4
H Avet-Loiseau
5
M De Braekeleer
6
S Salem
7
A Baruchel
1
SC Raimondi
8
SD Raynaud
7
1
Centre Hospitalier Universitaire (CHU) Saint
Louis, AP-HP, Paris, France;
2
The Chaim Sheba Medical Center,
Tel-Hashomer, Israel;
3
The Mount Sinai Medical Center, New York,
NY, USA;
4
New York Presbyterian Hospital-Cornell
Campus Cornell University Weill Medical
College, New York, NY, USA;
5
CHU Nantes, France;
6
CHU Brest, France;
7
CHU Nice, France;
8
Jude Children’s Research Hospital, Memphis,
TN, USA
References
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AML1 gene amplification: a novel finding in childhood acute
lymphoblastic leukemia. Haematologica 2000; 85: 362–366.
2 Busson-Le Coniat M, Nguyen Khac F, Daniel MT, Bernard OA, Berger R.
Chromosome 21 abnormalities with AML1 amplification in acute
lymphoblastic leukemia. Genes Chromosomes Cancer 2001; 32: 244–
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3 Dal Cin P, Atkins L, Ford C, Ariyanayagam S, Armstrong SA, George R
et al. Amplification of AML1 in childhood acute lymphoblastic
leukemias. Genes Chromosomes Cancer 2001; 30: 407–409.
4 Penther D, Preudhomme C, Talmant P, Roumier C, Godon A,
Mechinaud F et al. Amplification of AML1 gene is present in childhood
acute lymphoblastic leukemia but not in adult, and is not associated
with AML1 gene mutation. Leukemia 2002; 16: 1131–1134.
5 Morel F, Herry A, Le Bris MJ, Douet-Guilbert N, Le Calvez G, Marion V
et al. AML1 amplification in a case of childhood acute lymphoblastic
leukemia. Cancer Genet Cytogenet 2002; 137: 142–145.
6 Donadieu J, Auclerc MF, Baruchel A, Perel Y, Bordigoni P, Landman-
Parker J et al. French Acute Lymphoblastic Leukaemia Group (FRALLE).
Prognostic study of continuous variables (white blood cell count,
peripheral blast cell count, haemoglobin level, platelet count and age) in
mar(AML1++)
mar1 (AML1++)
mar1 (AML1++)
ab
de
c
Figure 1 FISH analyses using AML1 (red signal) and TEL (green
signal) probes. AML1 amplification was detected on interphase nuclei
(a–c) and metaphase chromosomes (d–e). Different patterns according
to karyotypes are shown: pseudodiploid (case 2, aand d), hyperdiploid
(case 13, band e), and karyotype failure (case 16, c). Arrows show
chromosomes with AML1 extra signals. Note that AML1 extra signals
are clustered in one area within interphase nuclei.
Correspondence
1681
Leukemia

childhood acute lymphoblastic leukaemia. Br J Cancer 2000; 83: 1617–
1622.
7 Martinez-Ramirez A, Urioste M, Contra T, Cantalejo A, Tavares A,
Portero JA et al. Fluorescence in situ hybridization study of TEL/AML1
fusion and other abnormalities involving TEL and AML1 genes.
Correlation with cytogenetic findings and prognostic value in children
with acute lymphocytic leukemia. Haematologica 2001; 86: 1245–
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8 Nordgren A, Heyman M, Sahlen S, Schoumans J, Soderhall S,
Nordenskjold M et al. Spectral karyotyping and interphase FISH reveal
abnormalities not detected by conventional G-banding. Implications for
treatment stratification of childhood acute lymphoblastic leukaemia:
detailed analysis of 70 cases. Eur J Haematol 2002; 68: 31–41.
9 Sun G, Qin N, Sun N, Close P, Wang S, Yang X et al. Intrachromosomal
amplification of AML1 gene in a pre-B-ALL in relapse detected
predominantly in interphase cells by FISH. Blood 2001; 98(Suppl):
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10 Mathew S, Rao PH, Dalton J, Downing JR, Raimondi SC. Multicolor
spectral karyotyping identifies novel translocations in childhood acute
lymphoblastic leukemia. Leukemia 2001; 15: 468–472.
Classification of mature T-cell leukemias
Leukemia (2003) 17, 1682–1683. doi:10.1038/sj.leu.2403003
TO THE EDITOR
We agree with Kussick et al
1
that not every case of T-cell leukemia is
easily classifiable. However, the only way forward in establishing
the correct diagnosis and improving the WHO classification is to be
able to define new disease entities. Currently, there are no data in
the literature, nor in their letter, to support the view that there is a T-
cell leukemia that should be classified as T-cell chronic lymphocytic
leukemia (T-CLL). Historically, the term ‘T-CLL’ was first used by
Brouet et al
2
in 1975, when they described patients who would now
be considered largely to be part of T-cell large granular lymphocytic
(T-LGL) leukemia and a few cases that we now call T-prolympho-
cytic leukemia (T-PLL). A large number of subsequent reports and
data emerging from the literature have allowed us to separate T-LGL
leukemia from T-PLL.
3,4
Since then, there has been no clear
evidence that a third entity, T-CLL, as proposed by Kussick et al,
1
indeed exists. We recognize that in T-PLL there is a degree of
morphological heterogeneity, which is already considered in the
WHO classification
5
and in our experience.
3–6
Therefore, the
classification of T-cell malignancies should not be based purely
on the morphological criteria but substantiated by the underlying
molecular/genetic features as well as clinical manifestations. Not all
T-PLL cases have circulating cells with the morphology of
prolymphocytes as in the classic 1974 description by Galton, which
is more applicable to B-cell PLL. Although the term ‘prolymphocyte’
may not be ideal to use in this condition, it has been retained for
historical reasons and indeed, provided everybody understands the
disease behavior and what this term defines, this should not be an
issue.
On reviewing the representative case #1 reported by Kussick
et al,
1
it is likely that this represents an example of small-cell variant
T-PLL, as defined by the WHO classification and as seen by us in
many patients;
3–6
the cells in the black and white illustration appear
typical, with cytoplasmic blebs, although a nucleolus is not
prominent, a feature that is common in the small-cell T-PLL variant.
The phenotype CD4+, CD7+, CD8would fit very well with T-PLL.
Unfortunately, the key investigation, chromosome analysis and/or
overexpression of TCL-1 or mutational analysis for ATM – features
also characteristic of T-PLL,
7–9
– have not been performed. A second
case in which no details are given does not add weight to their
argument.
We would also disagree that there is a conflict between the REAL
and the WHO classifications.
5,10
The REAL was an attempt to start
grouping cases into disease entities; there was no clear separation of
cases within the mature T-cell leukemias, but since that time-
extensive work has been carried out and a consensus reached
between pathologists and clinicians. The very high WBC of case #1,
500 10
9
/l, fits with the aggressive nature of the disease. We are not
given any details of follow-up but, in our experience, without
appropriate treatment, the median survival of T-PLL is 7 months.
3
We feel that there is no need to go back to old classification systems
in which no clear description of disease entities was given; this will
not serve any useful purpose for clinicians dealing with these
conditions. In particular, since Campath-1H (Alemtuzumab) ap-
pears to be the treatment of choice in T-PLL,
11,12
the correct
diagnosis of this disease becomes clinically relevant.
Although we recognize that there is a degree of morphological
heterogeneity in T-PLL, the data on cytogenetics and molecular
genetics are overwhelming, with 90% of patients having inversion
14(q11;q32) and abnormalities of chromosome 8 in 80%.
7,9
Further
advances will, of course, be welcome, but when one undertakes
such studies, there is a need to investigate the patients adequately
in every aspect – morphology, immunophenotype, cytogenetics
and clinical manifestations – and then submit the material to
further molecular analysis, for example, gene profiling. Such ad-
vances may or may not define new disease entities but will refine
the diagnostic criteria and point to genes relevant to pathogenesis.
In these and other conditions such as B-cell CLL, the way to progress
is to agree on the basic data and then move forward with the new
information.
E Matutes
1
D Catovsky
1
1
Academic Department of Haematology &
Cytogenetics, The Royal Marsden Hospital,
London, UK
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Received 14 March 2003; accepted 26 March 2003
Correspondence: Dr E Matutes, Academic Department of Haematol-
ogy & Cytogenetics, The Royal Marsden Hospital, Fulham Road,
London SW3 6JJ, UK; Fax: +44 20 7351 6420
Correspondence
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