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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1057-1062
Protracted and Variable Latency of Acute Lymphoblastic Leukemia After
TEL-AML1 Gene Fusion In Utero
By
Joseph L. Wiemels,
Anthony M. Ford,
Elisabeth R. Van Wering,
Aleida Postma, and
Mel Greaves
From the Leukaemia Research Fund Centre, Institute of Cancer
Research, London, UK; the Dutch Childhood Leukemia Study Group (DCLSG),
The Hague, The Netherlands; and the Beatrix Children's Hospital,
University of Groningen, Groningen, The Netherlands.
 |
ABSTRACT |
We report a pair of identical twins with concordant acute
lymphoblastic leukemia (ALL). Unusually, their diagnoses were spaced 9 years apart at ages 5 and 14. Leukemic cells in both twins had a
TEL-AML1 rearrangement, which was characterized at the DNA
level by an adaptation of a long distance polymerase chain reaction (PCR) method. The genomic fusion sequence was identical in the two
leukemias, indicative of a single cell origin in one fetus, in utero.
At the time twin 1 was diagnosed (aged 5 years), the bone marrow of
twin 2 was hematologically normal. However, retrospective scrutiny of
the DNA from an archived slide with clonotypic TEL-AML1 primers
showed that the presumptive preleukemic clone was present and
disseminated 9 years before a clinical diagnosis. These data provide
novel insight into the natural history of childhood leukemia and
suggest that consequent to a prenatal initiation of a leukemic clone,
most probably by TEL-AML fusion itself, the latency of ALL can
be both extremely variable and protracted. This, in turn, is likely to
reflect the timing of critical secondary events.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
PEDIATRIC ACUTE lymphoblastic leukemia
(ALL) is a biologically and clinically diverse cancer. The striking
age-associated peak incidence of disease in developed societies at 2 to
5 years of age is characterized as B-cell precursor or common (c)
ALL1,2 and within this group are molecular subgroups with
hyperdiploidy or karyotypically cryptic t(12;21), TEL-AML1
(ETV6-CBFA2) gene fusions.3,4 The etiology of ALL
is unknown. Recent evidence suggests exposure to ionizing radiation or
electromagnetic fields (EMF) are not major
factors.5,6 Epidemiologic studies, principally from the UK,
have implicated an abnormal response to common
infection(s).7,8 Key issues are the time frame of ALL
development and whether the consistent molecular abnormalities observed
are the product of primary or secondary etiological events. For infants
with acute leukemia and MLL gene fusions, there is now
compelling evidence for a prenatal initiation in utero. These data
derive from studies on identical twins9-11 and, more
directly, by retrospective detection using polymerase chain reaction
(PCR) of clonotypic genomic MLL-AF4 fusion sequences in
neonatal blood spots (Guthrie cards) of patients.12
The question of whether the more common form of childhood B-cell
precursor leukemia (cALL) can also be initiated in utero is much less
certain,13 although some mathematical modelling accords
with a prenatal origin.14 While some epidemiologic studies provide further support for an origin of infant acute
leukemia during pregnancy,15,16 there is
sparse evidence for such an association in typical childhood ALL other
than longstanding data indicating a small, but significant, increased
risk ( 1.4×) from diagnostic radiation exposure in
pregnancy.17,18 Changes in diagnostic procedures have
effectively removed this risk. There is some biological evidence
compatible with an in utero origin for cALL. For patients less than 3 years of age, the lack of N region nucleotides at the VDJ junctions of
rearranged IGH alleles of leukemic blast cells in most cases is
considered to reflect the minimal function of terminal deoxynucleotidyl
transferase (TdT) in fetal B lymphopoiesis.19,20 Recent
data from identical twin studies in ALL provides indirect, but
convincing, evidence for an in utero origin in at least some cases. We
described a pair of twins aged 3 years 6 months and 4 years 10 months
at diagnosis (with cALL) who shared a nonconstitutive, but identical or
clonotypic TEL-AML1 fusion, at the DNA level as well as an
identical rearranged IGH allele.21 As with
previous studies on other leukemias in twins,9,10,22
these data were interpreted as reflecting an in utero single-cell
origin of the TELAML1 fusion followed by prenatal
dissemination of the clonal progeny from one twin to the other via
intraplacental anastomoses.23,24
We now report another pair of identical twins with ALL that confirm the
fetal origins of the TEL-AML1 gene, but that are especially informative in the context of postnatal latency for ALL.
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MATERIALS AND METHODS |
Patients' obstetric and clinical history.
Female identical twins 244 and 2850 (Dutch Childhood Leukemia Study
Group) were born on April 9, 1968. They were diagnosed with ALL aged 5 years 2 months (twin 244) and 13 years 11 months (twin 2850) at the
Beatrix Children's Hospital. Twin 2850 had CD10+ B lineage
ALL (L2, common ALL) with normal cytogenetics; twin 244 was not
immunophenotyped or karyotyped, but morphologically and histochemically
was classified as ALL. The main hematologic parameters were as follows:
twin 244, white blood cell (WBC) count 6.6 × 109/L,
21% blasts, bone marrow 98% blasts. Twin 2850, WBC 4.8 × 109/L, 35% blasts, bone marrow 94% blasts. Twin 244 was
treated on protocol DCLSG ALL-2 and has remained in complete remission.
Twin 2850 was treated using protocol DCLSG ALL-5, relapsed after 20 months, and died in second remission of infection 9 months later.
Frozen bone marrow cells (94% blasts) taken at diagnosis were
available on twin 2850 and were found to be suitable for DNA, but not
mRNA extraction. For twin 244, the only diagnostic material available
was one bone marrow smear stained with Sudan Black and another stained
with periodic-acid Schiff (PAS). A stained bone marrow
smear was also available from twin 2850, which was made at the time of
the diagnosis of her twin, ie, 9 years before she herself was
diagnosed. This smear was at the time judged to be hematologically
normal. At the time of study, therefore, the slides available on the
twins had been kept for 15 years. The twins were identical in
appearance and had the same blood and HLA groups. The mother was 22 years old at the time of birth and received no diagnostic radiation
during pregnancy. The twins at birth had no congenital malformations,
and there was no family history of leukemia or related conditions.
There is no record of whether the placenta was monochorionic or dichorionic.
Preparation of DNA.
DNA was prepared from the bone marrow of twin 2850 essentially as
described in Ford et al.25 DNA was prepared from
PAS-stained bone marrow smears using TaKaRa Dexpat (BioWhitaker UK,
Wokingham, UK) exactly as described by the manufacturer
before being diluted further for PCR.
DNA was also isolated from an additional bone marrow slide prepared 8 years and 9 months before the onset of clinically diagnosed leukemia
from twin 2850. Half of the contents of the slide was scraped into an
eppendorf tube and treated with sodium dodecyl sulfate (SDS)-proteinase
K and extracted with phenol twice. DNA was ethanol precipitated and
dissolved in 20 µL of TE (10 mmol/L Tris-HCl, l pH 8.0, 1 mmol/L EDTA). DNA concentration was determined by GeneQuant
(Pharmacia, St Albans, UK). Three microliters was used for
subsequent PCR analysis.
Southern blot analysis of TEL rearrangement.
DNA from twin 2850 was digested with BamHI, electrophoresed
through 0.7% agarose, transferred to Hybond N+ (Amersham,
Bucks, UK) and hybridized to a cDNA probe corresponding to
TEL exon 526 essentially as described
previously.21
Long-distance inverse PCR (LDI-PCR).
With the AML1 gene still not completely sequenced, there is a
need for a rapid method for cloning and sequencing of TEL-AML1 fusion regions. Therefore, we have adapted an LDI-PCR method for this
purpose. A similar approach has been used previously for rapid cloning
of IGH gene rearrangements.27 DNA from twin 2850 was subjected to LDI-PCR analysis for genomic TEL-AML1 fusion by the methodology described by Willis et al.27 Briefly,
0.5 µg of twin 2850 DNA was digested with 5 U HindIII
overnight in parallel with a normal control. Digested DNA was extracted
by an equal volume of phenol followed by ether. DNA was diluted to 0.5 mL, then subjected to treatment with 5 U T4 DNA ligase overnight. The
dilute nature of the DNA favors intramolecular ligation
(circularization) of DNA fragments rather than intermolecular ligation.
Ligated DNA was then purified in Qiagen spin columns and dissolved in 40 µL of TE. The circularized fragments were subjected LDI-PCR using
primers inv3A and inv3B (Table 1, Fig 1A).
Six picomoles of each primer was added to 1 µL DNA in 60 mmol/L
Tris-SO4 (pH9.1), 18 mmol/L
(NH4)2SO4, 1.7 mmol/L
MgSO4, 200 µmol/L each deoxynucleotidyl triphosphate
(dNTP), and 0.5 µL Elongase enzyme (GIBCO-BRL, Paisely, UK) in a 50-µL reaction. Tubes were cycled 35 times, 30 seconds at 94°C, 30 seconds at 66°C, and 18 minutes at
68°C. A total of 1 µL of this reaction was then subjected to a
nested reaction using primers inv3A-1 and inv3B-1 using the same PCR
conditions.
Using NotI sites present in the nested primers, PCR products
from the second reaction were cloned into the NotI site of
pBluescript (Stratagene, Amsterdam, The Netherlands) and
sequenced with forward and reverse universal primers (automated
sequencing on an ABI 373a sequencer). Additional sequencing primers
were used as needed to sequence the entire HindIII fragment. On
identification of the translocation breakpoint, additional primers were
synthesized to amplify both the TEL-AML1 and the reciprocal
AML1-TEL translocation from both twins. Primers T28TELA and
T28AMLB were used for the former and T28AMLA and T28TELB for the latter
(Table 1). A total of 10 ng of twin 2850 DNA and 1 µL of a 1:100
dilution (in TE buffer) of twin 244 DNA was used for PCR (20 pmol each
primer, 50 mmol/L KCl, 10 mmol/L Tris-HCl, 2.5 pmol each dNTP, and 2.5 U of Taq polymerase [Perkin Elmer, Warrington,
UK]), 35 cycles 94°C for 1 minute, 64°C for 1 minute, and 72°C for 1 minute followed by 10 minutes at 72°C).
A heminested reaction for both translocations was then performed using
the same sense primers (T28AMLA, T28TELA), but a proximal antisense
primer (T28AMLB-1, T28TELB-1) for the two separate reactions. PCR
products were purified by agarose gel electrophoresis and directly
sequenced with the PCR primers.
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RESULTS |
Twin 2850 was identified as having a TEL rearrangement in
intron 5 by Southern blotting (data not shown). LDI-PCR was applied to
various TEL intron 6 restriction fragments, and a product
differing in size from the normal genomic product was identified using
a HindIII digest and inv3 primers
(Fig 1A). This product was cloned and
sequenced, yielding TEL sequence on one side and
non-TEL on the other. Using a BLAST sequence similarity search,
it was discovered that the breakpoint was located just before exon 2 of
AML1 (Fig 1B). To confirm the TEL-AML1 translocation,
primers T28TELA and T28AMLB were used to amplify a 488-bp amplicon in
twin 2850 (data not shown). This product was sequenced and found to be
identical to the LDI-PCR product. Using one of the stained slides from
twin 244, we were unable to amplify this product even using the
heminested reaction (T28TELA and T28AMLB-1, which yields a 419-bp
product); the size of the amplicon could not be reduced due to the
presence of an Alu sequence in TEL immediately
preceding the breakpoint (Fig 1B). Therefore, we attempted to amplify
the AML1-TEL reciprocal fusion product from twin 244 slide DNA.
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| Fig 1.
Analysis of TEL/AML1 translocations in concordant
twin leukemias. (A) Long-distance inverse PCR analysis of an intron 5 TEL HindIII fragment of normal control (CON) and
leukemic (T-2850) DNA. The expected band size is 4.2 kb, patient T-2850
exhibited a 1.3-kb band. (B) Schematic of the normal TEL and
AML1 genes along with the TEL/AML1 translocation in
T-2850. The inv3 primers anneal to the 5' end of the 4.2-kb
HindIII fragment as shown; the translocation brought a
HindIII site of AML1 closer to the inv3 primer sites
than the normal HindIII site in TEL. The location of an
Alu repeat sequence in TEL is shown, as well as exon 2 of AML1. A large arrow indicates the translocation breakpoint.
(C) PCR analysis of the reciprocal AML1/TEL translocation in
the twins. The 411-bp heminested PCR product was amplified in both
twins, but not in control DNA samples. A total of 10 ng of T-2850 and 1 µL of a 1:100 dilution of DNA isolated from the T-244 slide was
amplified, along with 50 ng of control DNA samples. CON-1 is DNA from a
normal healthy individual, CON-2 and CON-3 are DNA samples from other
pediatric leukemia patients that also had TEL/AML1
translocations by RT-PCR. (D) Sequence surrounding the translocations
in the twins. Normal TEL is shown at top and bottom and
AML1 in the center. TEL/AML1 is indicated by der 12 and
AML1/TEL by der 21. The duplicated "GTT" at the
breakpoint site is shown in bold, a Y is shown at the center nucleotide
in the der 21 sequence to indicate the T  C mutation in
T-244. The bottom sequence of TEL is shifted 44 nucleotides to
the left to indicate a 47-bp deletion on translocation.
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PCR using primers T28AMLA and T28TELB, followed by a heminested
reaction with T28AMLA and T28TELB-1, yielded a 411-bp product in both
twin 2850 and 244, and not in normal or leukemic control DNA (Fig 1C).
On sequencing these products, it was noted that there was an apparent
117-bp deletion in TEL, as well as several point mutations when
compared with the database sequence of TEL (Genbank HSU61375).
However, on PCR amplifying and sequencing the TEL genomic
sequence of this region from DNA samples from several individuals, we
found that the majority had the variant sequence also found in the
twins (data not shown). This region is therefore polymorphic. When
comparing both the TEL-AML1 sequence and the reciprocal
AML1-TEL, there was a 47-bp loss of TEL sequence in the
process of translocation. In contrast, the sequence "GTT," a part
of the germ line AML1, was duplicated and present in both translocations of twin 2850. Twin 244 had the identical sequence of the
AML1-TEL as twin 2850, but interestingly, had a T C
point mutation at the center thymidine of the repeated "GTT" (Fig
1D). This is unlikely to be a PCR artefact, as we have been able to amplify and sequence it in independent repeat PCR reactions. This mutation, probably occurring during clonal evolution, is also a useful
indicator of lack of contamination between the twin samples.
A bone marrow aspirate was taken and a stained smear prepared from twin
2850 at the same time that twin 244 was diagnosed with leukemia, ie,
when the twins were 5 years old. This was considered hematologically
normal. A total of 27 ng of DNA was isolated from half of this slide.
The DNA was analyzed by PCR using the heminested primer set to the
AML-1-TEL translocation as used on the diagnostic slide from
twin 244 (Fig 1C). DNA from the bone marrow slide was positive for the
translocation (Fig 2), thus demonstrating
the detection of the leukemic clone more than 8 years before clinical disease. The sequence was identical to that found in twin 2850 in DNA
isolated at the time of diagnosis.
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| Fig 2.
Analysis of the AML-1-TEL translocation in a bone
marrow smear 8 years and 9 months before diagnosis of leukemia. The
411-bp heminested AML-1-TEL PCR product was amplified from 10 ng of diagnostic DNA from T-2850 (T-2850, diag.) and 4 ng of DNA
isolated from a stored bone marrow smear prepared 8 and a half years
before diagnosis (T-2850, slide). Lanes containing 50 ng of DNA from
normal controls (CON-1, CON-2) were negative.
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DISCUSSION |
TEL-AML1 translocations are characterized at the genomic level
by breaks in a restricted region of TEL (intron 5) and in a very large, and currently unsized, region of AML1 (intron 1 or 2). We took advantage of this by cloning the translocation breakpoint using inverse primers from the TEL side. Inverse PCR has been used previously for identifying sequences flanking transposon insertion
sites,28 exon/intron border sequences, and for
identification of IGHJ fusion partners in
leukemia/lymphoma.27 We will report a more complete
description of the technique as applied to the cloning of
TEL-AML1 translocations elsewhere (JW and MG, submitted).
The TEL-AML1 gene fusion, in common with other hybrid
recombinations in leukemia, involves intronic DNA breaks that are
clustered, but diverse.29,30 As a consequence, each patient
and each leukemic clone has a unique or clonotypic genomic fusion
sequence. TEL-AML1 and other gene fusions are acquired,
nonconstitutive abnormalities and so the finding that leukemic cells
from identical twins share the same clonotypic sequence is most
plausibly interpreted as reflecting a single cell origin of the double
leukemia and a shared clone. As in previous molecular studies with
leukemic cells in identical twins, there is only one likely basis for a
shared clone and that is with a fetal origin in one twin followed by
prenatal intraplacental metastasis of clonal progeny from that twin to the other. A common leukemic clone identified by unique genotype has
now been recorded for five infant twin pairs with ALL (four pairs) or
AML (one pair) and MLL gene fusions,9-11 a twin
pair of children with T-ALL/T-non-Hodgkin's lymphoma
(NHL),22 and one previous pair of twins with
ALL and a TEL-AML1 fusion.21 The present data
confirm in an additional twin pair that the TEL-AML1 can
originate in utero. These data further reinforce the point that
TEL-AML1 fusion can be a very early molecular event and quite possibly represents the first or initiating mutation in B-cell precursor ALL. Moreover, because there is no reason to suppose that
this can only occur in the context of a twin pregnancy, we conclude
that this common molecular abnormality must also arise prenatally in at
least some nontwin children with ALL.
The concordance rate for ALL in noninfant twins is not known, but we
calculate from our twin survey in the UK over the past 10 years that it
may be around 5% or 1 in 20 (unpublished observations, December
1998). Ninety-five percent discordance therefore requires an explanation and there are two different possibilities to be considered: first, that 95% of ALL in children, twin and nontwin, are
initiated postnatally; second, that ALL in children is usually initiated prenatally, but some secondary postnatal event is required for which twins are more likely than not to be discordant.
Retrospective scrutiny of neonatal blood spots (Guthrie cards) of cALL
patients12 may resolve this issue.
The present twin pair provides new and unexpected insight into the time
frames that can be required for critical sequential events in the
common subtype of childhood ALL. The data clearly suggest that after an
in utero initiation, the subsequent latency of the clinical development
of leukemia can be very protracted, 14 years in the case of one of
these twins. Moreover, in the latter case, we were able to
retrospectively identify the presence of the clonotypic
TEL-AML1 genomic fusion sequence in a hematologically normal
bone marrow smear made 9 years before the subsequent diagnosis of ALL
in this twin. This result suggests that the presumptive preleukemic
clone may have been disseminated in the marrow. At the same time, this
clone was clearly restrained in its net growth advantage and
pathological impact for almost a decade. These data therefore provide
some support for the suggestion13 that the natural history
of pediatric ALL may parallel balanced chimerism in chronic myeloid
leukemia (CML) evolving eventually to an acute leukemic
blast crisis. Unfortunately, we were not able to quantify the number of
TEL-AML1 positive cells in the bone marrow at this time and
cannot comment therefore on how widespread the dissemination of the
preleukemic clone may have been or what degree of clonal advantage may
have been accrued (over 5 years) from the initial TEL-AML1 fusion event. As we required two rounds
(nested) of PCR to see a signal (compared with a single round for a
control gene, GSTmu), we assume that only a small number of cells were
present. With what little material remained (one half of a stained
smear), we attempted to enumerate cells with the TEL-AML1
fusion gene by two-color fluorescent in situ hybridization
(FISH), but unfortunately, the aged stained smears do not
provide interpretable signals with the TEL and AML1
probes available (ie, compared with fresh material) (C. Harrison,
J.L.W., and M.G., unpublished observations, August 1998).
Although documentation of a 14-year period of latency in childhood ALL
is unprecedented, we have reported another twin pair with monoclonal
T-cell malignancy diagnosed at age 9 and 11 years.22 Adult
epithelial cancers are generally recognized as having an evolutionary
time frame of decades, and this is deemed to reflect the time scale
required for the accumulation of a complementary set of mutations and
any associated exposures that facilitate these events. Leukemias, not
having to escape the confines and restraints of fixed tissue
architecture, may require fewer genetic events and therefore could
evolve to malignancy over a shorter time frame. For children who
develop acute leukemia as a consequence of a known genotoxic exposure,
for example, with cancer therapy (chemotherapy or
irradiation)31 or after the atomic bombs in Japan,18,32 the period of excess risk, reflecting variable latency, is mostly in the range of 1 to 10 years; the maximum risk and
average latent period varying with type, pattern, and level of exposure
(overall average 5 years). A 14-year postnatal latency for childhood
ALL is therefore very protracted, but not incompatible with prior data.
It does, however, raise the possibility hitherto not seriously
considered that, even for older children with leukemia, the disease may
have a prenatal origin. The great majority of ALL cases with
TEL-AML1 fusion are between 2 and 10 years of age; only a few
cases are recorded between 10 and 15 years of age33 or in
adult ALL.34 This indicates that if, as we suggest,
TEL-AML1 may be a common prenatal initiating event, then a
14-year latency, as in the twin case here, is unusual and represents
the tail end of an age-associated risk.
The other twin in the current pair was diagnosed aged 5 years 2 months,
8 years 9 months before her twin sister. Such a diversity of age at
diagnosis is unusual in concordant twin leukemias in children.
Simultaneous diagnosis is the norm for infant twins with acute
leukemia,9 although the second twin may have a diagnosis derived from hematologic and molecular evidence in the absence of
clinical symptoms.35 We have now studied a total of 11 pairs of noninfant twin children with cALL, although not all have been molecularly characterized. Their average age at diagnosis is no different from that of nontwin children with cALL (3 to 4 years) and
the average difference in the timing of onset of clinical symptoms is
around 18 months (unpublished observations, December 1998). The striking difference in the postnatal latency
period in the present twin pair most probably reflects that necessary secondary events required for the development of overt leukemia within
the clone of preleukemic cells spawned prenatally were independently
acquired at very different times. This situation could arise if such
events occur entirely by chance or if they require promotion by
particular patterns of exposure, such as infection, that can occur
intermittently.8,36 Ongoing epidemiological case/control
studies may shed some light on these possibilities.
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ACKNOWLEDGMENT |
We thank Dr T.G. Willis for discussions of the LDI-PCR method and
Barbara Deverson for help in preparation of the manuscript.
| |
FOOTNOTES |
Submitted January 15, 1999; accepted March 30, 1999.
Supported by the Leukaemia Research Fund.
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.
Presented at the American Society of Hematology Meeting, held in Miami
Beach, FL, December 4-8, 1998, and published as an
abstract in Blood 92:68a, 1998 (suppl 1).
Address reprint requests to Professor Mel Greaves, PhD, Leukaemia
Research Fund Centre, Institute of Cancer Research, Chester Beatty
Laboratories, 237 Fulham Rd, London SW3 6JB, UK; e-mail:
m.greaves{at}icr.ac.uk.
| |
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