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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3362-3367
The Presence of Typical and Atypical BCR-ABL Fusion Genes in
Leukocytes of Normal Individuals: Biologic Significance and
Implications for the Assessment of Minimal Residual Disease
By
Shikha Bose,
Michael Deininger,
Joanna Gora-Tybor,
John M. Goldman, and
Junia V. Melo
From the LRF Centre for Adult Leukaemia, Department of Haematology,
Imperial College School of Medicine, Hammersmith Hospital, London, UK.
 |
ABSTRACT |
The number of genetic lesions necessary to generate leukemia in
humans is unknown, but it is possible that certain specific abnormalities, eg, fusion genes, known to be associated with acute and
chronic leukemia are produced relatively frequently in human cells but
require other events to occur before the leukemia becomes manifest. We
investigated this possibility by studying peripheral blood leukocytes
from normal individuals and various hematopoietic cell lines for the
presence and expression of the p210 and the p190 types of the BCR-ABL
gene associated with chronic myeloid leukemia (CML) and acute
lymphoblastic leukemia. We used two-step reverse
transcriptase-polymerase chain reaction (RT-PCR) assays in which
batches of 108 cells per sample were tested in 40 replicate
reactions. We estimate that this assay is 1.5 logs more sensitive than
the two-step RT-PCR assays that we use routinely to assess minimal
residual disease. BCR-ABL fusion gene transcripts of various
configurations were found in circulating leukocytes from 12 of the 16 healthy adults analyzed. Transcripts with an e1a2 junction (p190
BCR-ABL) were present in 11 and p210-type transcripts with b2a2
and/or b3a2 junctions were detected in 4 individuals. The same
RT-PCR assays in non-CML cell lines showed the presence of classical or
aberrant p210-type mRNA in 3 of 7 lines and of p190-type transcripts in all 7 lines of hematopoietic origin (HL60, KG1, U937, Kasumi, Jurkat,
JVM13, and JVM25), whereas the NIH3T3 murine fibroblast line was
reproducibly negative for these fusion genes. These findings confirm
and extend previous reports on the detection of leukemia-associated genes in normal leukocytes and suggest that certain fusion genes are
generated relatively frequently in hematopoietic cells, but only
infrequently do the cells acquire the additional changes necessary to
produce leukemia in humans. Although there is only a small probability
that such innocent BCR-ABL-carrying leukocytes are detected by
conventional RT-PCR assays, they may be the source of some sporadically
positive tests in leukemia patients in long-term remission.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THE DEMONSTRATION OF the t(9;22)(q34;q11)
chromosomal translocation and/or of the BCR-ABL fusion gene in
hematopoietic cells from patients with clinical features of a chronic
myeloproliferative disease usually establishes the diagnosis of chronic
myeloid leukemia (CML). Likewise, the presence of BCR-ABL in the blast
cell population of patients with acute leukemia is generally accepted
as the molecular basis of Philadelphia (Ph)-positive acute
lymphoblastic leukemia (ALL) or, more rarely, acute myeloblastic
leukemia (AML). In CML, the breakpoint in the BCR gene nearly always
occurs in the major breakpoint cluster region (M-bcr), and the
resultant BCR-ABL mRNA molecules with a b2a2 or a b3a2 junction encode
a p210BCR-ABL fusion protein. In two thirds of
Ph+ ALLs, the BCR breakpoint falls in the minor breakpoint
cluster region (m-bcr) and the hybrid BCR-ABL transcript
contains an e1a2 junction and is translated as a
p190BCR-ABL product.1 The fact that both
BCR-ABL fusion proteins can induce a CML-like or an acute
lymphoproliferative disease in murine models2-4 provides
strong evidence of their fundamental causal role of these leukemias in
humans.
It is estimated that patients with leukemia have a total burden of more
than 1012 malignant cells in the body at
presentation,5 and the overwhelming majority of their
circulating leukocytes harbor the fusion gene. The kinetics of
expansion of the BCR-ABL-containing clone during the preclinical stage
are not known, because this clone is usually identified only when the
leukemia becomes overt. There is some indirect evidence that the
formation of the BCR-ABL hybrid gene may not be the initial or the sole
event in the development of CML. For example, studies of allelic
biochemical markers in Epstein-Barr virus (EBV)-transformed B cells
from chronic-phase CML show that most clones expressing the same
markers as the malignant clone have a high frequency of cytogenetic
abnormalities; however, they may not contain the t(9;22)
translocation.6 Similarly, we and others7-9
have observed a number of patients who, after treatment with
interferon- , achieve a complete cytogenetic response, as defined by
the disappearance of Ph+ metaphases, but show the emergence
of another clone with a different chromosomal abnormality. These cases
may reflect the existence of a pool of secondary, weaker clonal
mutations in the background of chronic-phase CML, which only becomes
visible when the predominant t(9;22)-positive clone is suppressed.
Overall, the data suggest that the pathogenesis of CML, like that of
most types of cancer, is multistep.
The idea that BCR-ABL, and perhaps other fusion genes, may be formed
inconsequently in hematopoietic cells, ie, without necessarily leading
to a selective growth advantage, was strengthened recently by two
studies. The first was the report by Biernaux et al10 on
the detection of hybrid BCR-ABL mRNA transcripts in leukocytes from
approximately 30% of normal adults. The second piece of evidence comes
from our observation that various types of leukemia-associated fusion
genes are generated at low frequency in some hematopoietic cell lines
in standard culture conditions in the absence of specific mutagenic
stimuli.11 We have now extended this line of investigation by analyzing peripheral blood leukocytes from healthy individuals as
well as a series of Ph hematopoietic cell lines for
the presence of BCR-ABL fusion transcripts of the CML (p210)
and/or the ALL (p190) types. We show here that a low background
of BCR-ABL hybrid gene formation can be actually detected in leukocytes
from the majority of normal adults and in non-CML cell lines, with a
strong predominance for the p190 type of fusion.
| |
MATERIALS AND METHODS |
Blood samples.
Sixteen healthy subjects were studied, a group composed of 7 male and 9 female laboratory workers aged 23 to 46 years of age (mean ± SD = 33 ± 7 years of age). A single donation of 100 to 120 mL peripheral
blood was obtained from each individual after informed consent was
obtained, and the samples were immediately coded to ensure anonymity of
the donors. The blood specimen was subjected to red blood cell
lysis,12 and the isolated white blood cells (WBCs) were
washed twice in phosphate-buffered saline (PBS) and lysed in a
guanidinium thiocyanate (GTC) solution.13 Multiple aliquots
of GTC lysates corresponding each to 107 WBCs were stored
at  80°C until processed for RNA extraction.
Cell lines.
Seven human hematopoietic cell lines and one murine fibroblast line
(NIH-3T3) were analyzed in this study. The former group was composed of
KG1, HL60 and Kasumi (AML lines), U937 (histiocytic lymphoma), Jurkat
(T-ALL), JVM13 (B-prolymphocytic leukemia), and JVM25 (EBV-immortalized
normal lymphoblastoid line). Stocks from all these cell lines were
analyzed by conventional cytogenetics and fluorescence in situ
hybridization (FISH) with BCR and ABL probes14 to confirm
the absence of a t(9;22). Cells from exponentially growing cultures of
these lines were harvested, washed in PBS, and lysed in GTC for storage
as described above.
Reverse transcriptase-polymerase chain reaction (RT-PCR) assay.
RNA extraction and reverse transcription were performed as previously
reported.13,15 The 40 µL cDNA synthesis from each 107 cell aliquot was diluted in distilled H2O
to 80 µL, and 1 µL was tested for quality control in a one-step PCR
amplification of normal ABL sequences.16 The remaining 79 µL cDNA from each of 10 × 107 cell aliquot was then
divided into 4 × 100 µL PCR tests for the first-step
amplification of a given fusion gene transcript, followed by a
second-step (nested) amplification of 1 µL first-step products. Separate amplifications of p210- and p190-type BCR-ABL transcripts were
performed with primers, reaction composition, and thermocycling conditions as previously described17
(Fig 1). Positive controls for these PCRs
were diluted cDNA preparations from the BV173 (for p210 BCR-ABL) and
the SD1 (for p190 BCR-ABL) cell lines, previously standardized in our
single-test diagnostic protocols for reproducible detection of 1 leukemia cell in 105 to 106 nonhematopoietic
cells (murine fibroblasts).
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| Fig 1.
Schematic representation of the types of
leukemia-associated BCR-ABL transcripts that can be amplified in the
two PCR protocols. Primers for first-step and second (nested)-step
amplifications are indicated as arrows over the exon regions
corresponding to their sequences. The upper diagram shows the BCR gene
structure according to Chissoe et al29 and the major and
minor breakpoint cluster regions (M-bcr and m-bcr,
respectively). Because of the position of the BCR primers, the p210 PCR
assay can only detect transcripts derived from breaks in M-bcr,
whereas the p190 PCR assay is able to amplify fusion transcripts
arising from breakpoints in either m-bcr or M-bcr (ie,
from alternative splicing of the primary M-bcr derived
message).
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Each batch of PCR tests contained 40 tubes of test cDNAs from 10 cell
aliquots, 1 tube with the positive control cDNA, and 4 negative
controls derived from the RNA extraction, cDNA synthesis, and
first-step and second-step PCR blanks. Extensive precautions were taken
to avoid the risk of PCR contamination. The six stages of cell
preparation, RNA extraction, cDNA synthesis, first-step PCR,
second-step PCR, and electrophoresis of PCR products were each
performed in six separate laboratory rooms in dedicated laminar air-flow cabinets. Mixes of reagents for cDNA synthesis and PCR amplification were prepared in bulk and stored as single-use aliquots with dedicated pipettes and plugged tips, in a PCR-free laboratory, by
personnel not involved with handling cells and/or actual PCR procedures. Aliquots from all mixes were extensively tested on mock
45-tube PCR assays containing no DNA template (H2O blanks) before and at various intervals during the period of testing of actual
cellular material and were always found to be contamination-free. A
murine cell line (NIH-3T3) representing a source of cellular RNA from
which amplification of a human BCR-ABL message could definitely not
occur was used as a reliable negative control for contamination.
Five microliters of the second-step PCR products were electrophoresed
through ethidium-bromide stained agarose gels, visualized, and
photographed under UV light. In view of the extensive and comprehensive
negative controls included for every procedure in this study, a sample
was scored as positive if any of the 40 tests produced an amplified
product. For confirmation of the BCR-ABL nature of these products,
representative fragments of each individual size were gel-purified and
sequenced by conventional methods.
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RESULTS |
In this study, we investigated the possibility that BCR-ABL fusion
genes are generated at low frequency in vivo and/or in vitro in
rare cells from within a t(9;22)-negative cell population. To detect
these postulated rare events, we analyzed the total amount of cDNA
synthesized from 108 normal WBCs or from
Ph cell lines in 40 replicate PCR tests for the
presence of p210- or p190-type fusion mRNA transcripts
(Fig 2). The results of these tests are
presented in Tables 1 and
2.
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| Fig 2.
Representative RT-PCR screening for p190 BCR-ABL
transcripts in leukocytes from a healthy adult. The
ethidium-bromide-stained agarose gels show quadruplicate PCRs (labeled
a, b, c, and d) for each cDNA aliquot (labeled 1 through 10) including
1 of the 4 negative (Neg.) controls and 1 positive (P) control specimen
(SD1 cell line). The first lane on each gel is a 123-bp DNA ladder
marker.
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BCR-ABL fusion transcripts of the p210 type were detected in leukocytes
from 4 of 15 (27%) normal individuals and in 3 (HL60, KG1, and Jurkat)
of the 7 hematopoietic cell lines tested, but never in the NIH-3T3
murine fibroblast line. In 3 individuals and in the Jurkat cell line, 2 to 3 of the 10 cell aliquots yielded positive bands in more than 1 of
the 4 PCR replicates; in the fourth healthy subject, as well as in HL60
and KG1, amplification products were observed in only 1 of 10 cell
aliquots. Fusion transcripts with classical b2a2 and/or b3a2
junction were detected in all 4 positive individuals, and in 2 of
these, additional hybrid molecules with unusual junctions, such as
b4a2, b5a2, and e17a2, were also coexpressed. Jurkat cells exhibited
b3a2 transcripts, whereas in KG1 and HL60, PCR products of larger sizes
were found, representing mRNA molecules with variable fragments of ABL
intron 1a inserted between BCR exon b5 and ABL exon a2
(Fig 3A).
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| Fig 3.
Representative second-step RT-PCR products of the
different types of BCR-ABL fusion transcripts detected in leukocytes
from normal individuals and non-CML cell lines. The BCR-ABL junction is
represented by a double-headed arrow ( ). (A) p210-type transcripts:
1 = BCR ex.b2 ABL ex.a2 and BCR ex.b3 ABL ex.a2; 2 = BCR
ex.b4 ABL ex.a2; 3 = BCR ex.b5 ABL ex.a2; 4 = BCR ex.b2 ABL ex.a2; 5 = BCR ex.b3 ABL ex.a2; 6 = BCR ex. e17 ABL
ex.a2; 7 = BCR ex.b5 ABL ex.a2; 8 = BCR ex.b3 ABL ex.a2; 9 = BCR ex.b5 153 bp of ABL intron 1a + ex.a2; 10 = BCR ex.b5
ex.a2; 11 = BCR ex.b2 ABL ex.a2; 12 = BCR ex.b3 ABL
ex.a2; 13 = BCR ex.b4 ABL ex.a2; 14 = BCR ex.b2 ABL ex.a2.
(B) p190-type transcripts: 1 = BCR ex.e1 ABL ex.a2; 2 = BCR
ex.e1 + 56 bp of intron 1 ABL ex.a3; 3 = BCR ex.e2
ABL ex.a3; 4 = BCR ex.5 ABL ex.a3; 5 = BCR ex.e1 ABL
ex.a2; 6 = BCR ex.e4 ABL ex.a2; 7 = BCR ex.e1 + 108 bp of
intron 1 ABL ex.a2; 8 = BCR ex.e1 ABL ex.a2; 9 = BCR
ex.e4 ABL ex.a2; 10 = BCR ex.e1 + 46 bp of intron 1 ABL ex.a2; 11 = BCR ex.e2 ABL ex.a2; 12 = BCR
ex.e1 + 172 bp of intron 1 ABL ex.a2; 13 = BCR ex.e1 ABL
ex.a2; 14 = BCR ex.e1 + 246 bp of intron 1 213 bp of ABL intron
2 + ex.a3.
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RT-PCR tests with primers designed to amplify predominantly the p190
type of BCR-ABL transcripts yielded positive results in 11 of 16 (69%)
of the healthy subjects and in all 7 hematopoietic cell lines. Only 1 of the 4 individuals positive for the p210 type of transcripts did not
show coexpression of the p190 type of message. Four batches of NIH-3T3
murine fibroblasts tested on different occasions during this study were
reproducibly negative in a total of 160 PCRs. In the normal adults
testing positive, the number of cell aliquots with detectable products
varied from 1 to 7 of 10 and in approximately one fourth of these cell
aliquots amplified fragments were obtained in at least 2 of the 4 replicate PCRs. The 7 hematopoietic cell lines showed 1 to 9 cDNA
aliquots with p190 amplification products, almost invariably in
replicate PCR tests. The majority (74%) of the transcripts had the
expected e1a2 junction, but in 7 samples larger fragments were also
observed. These were shown upon sequencing to represent BCR-ABL
transcripts with atypical junctions such as e2a2, e2a3, e1a3, e4a2, and
e5a3 and fusions containing BCR and/or ABL intronic sequences
in various rearrangements between e1 and a2 (Fig 3B).
| |
DISCUSSION |
In simplistic terms, the two equations CML = BCR-ABL and BCR-ABL = CML
(or Ph+ ALL) are generally valid. The first means that,
with rare and questionable exceptions,18 all patients with
bona fide CML have a BCR-ABL rearrangement in their malignant cell
clone. The second implies that the finding of a BCR-ABL fusion gene in
hematopoietic cells from an individual is a sign of impending or overt
CML (or Ph+ ALL, AML, etc). Similar equations could in fact
be proposed for other types of leukemias that are now known to be
consistently associated with specific types of fusion genes.
The results of the present study and those of Biernaux et
al10 provide a different perspective on the second
equation. Thus, we show here that BCR-ABL hybrid genes are formed and
transcribed in leukocytes from greater than two thirds of healthy
adults. Fusion transcripts with b2a2 or b3a2 junctions, the
characteristic configurations of CML, were detected in 27% of the
subjects tested, a frequency very similar to that found by Biernaux et
al10 in their analysis of a larger adult population.
Moreover, when we used an additional PCR protocol with primers that
enable the amplification of the hybrid mRNA molecules
typically found in Ph+ ALL, ie, those with an e1a2
junction, BCR-ABL fusion transcripts with this structure were detected
in the majority (69%) of normal individuals. Similar findings were
observed in the screening of 7 non-CML hematopoietic cell lines, all of
which expressed one or more types of BCR-ABL hybrid transcripts.
The difference in the frequency of detection of p210 and p190 type of
transcripts has several possible explanations. The most likely is that
BCR-ABL fusion genes derived from an m-bcr breakpoint, from
which only e1a2 chimeric mRNA can be transcribed, are generated more
frequently both in vivo (normal leukocytes) and in vitro (cell lines)
than those derived from M-bcr breakpoints. Such a bias at the
primary stage of genetic recombination before the influence of growth
advantage selection processes has been also observed upon exposure of
hematopoietic cell lines to high-dose ionizing radiation, where the
formation of some but not other forms of leukemia-associated fusion
genes can be induced.11 Alternatively, in some or all
normal individuals and non-CML cell lines the BCR-ABL gene might be
derived from a M-bcr breakpoint and might produce both
b2a2/b3a2 and e1a2 mRNA molecules by alternative splicing of the
primary RNA transcript (Fig 1). In this scenario, the higher frequency
of cases expressing only e1a2 type of transcripts would be due either
to an unknown mechanism preferentially favoring the e1a2 form of
splicing or to a technical artifact resulting from possible different
sensitivities of the two PCR assays. We think the latter is unlikely,
because extensive semiquantitative PCR titrations of the individual
p210 and p190 protocols have shown them to have a comparable level of
sensitivity.17
Taken together, our present findings confirm and extend those from
Biernaux et al10 and the reported observations of BCL2-IgH fusion transcripts in leukocytes from healthy subjects19,20 and provide strong evidence that the mere generation of specific chromosomal translocations and gene fusions is not sufficient to cause
a malignant process. These data have important biological and clinical
implications. From the point of view of leukemogenesis, they suggest
that such forms of illegitimate genetic recombination occur regularly
in hematopoietic precursors and in cultured cell lines as a consequence
of an inherent, basal level of genomic instability. To be successful in
producing a leukemic phenotype, these fundamental errors of DNA
replication and repair have to fulfill at least two criteria: (1) the
fusion gene structure must allow for the production of a functional
protein with direct or indirect oncogenic properties and (2) the
chromosomal translocation must occur in a relatively early precursor
cell with self-renewal capacity. In other words, only the combination
of a correct fusion gene in the correct primitive hematopoietic
progenitor has a potential selective advantage and can become
successful as an expanding clone. It is also possible that for some
types of leukemia, of which CML may be one,21 additional
mutations need to be accumulated in the affected cell clone before a
true malignant expansion can occur. It is likely therefore that the
BCR-ABL genes detected in the circulating leukocytes from healthy
individuals do not reflect incipient leukemia, because they were
generated in relatively mature, harmless progenitors from which the
derived clones are eventually lost through normal cell differentiation
and death. An alternative possibility is that in the overwhelming
majority of normal persons the immune system is able to recognize and
to eliminate the BCR-ABL expressing cells shortly after their
generation and initial period of replication, preventing their
uncontrolled expansion as a malignant clone. It is also interesting to
note that several of the BCR-ABL transcripts detected in normal
leukocytes and in the non-CML cell lines have an aberrant structure due
to wrong junctions between BCR and ABL exons or to the insertion of
intervening sequences; such genes would encode truncated BCR-ABL proteins that would presumably not be able to promote cell growth advantage. Because they are nonleukemogenic, only rarely are these aberrant BCR-ABL transcripts found in CML or ALL patient
samples,22,23 and in these instances they are always
secondary to the main, correctly spliced type of message.
From the clinical point of view, the detection of BCR-ABL transcripts
in healthy subjects could in principle raise concern as to the
significance and validity of the evaluation of minimal residual disease
in CML and Ph+ ALL by PCR assays. To dispel these doubts,
it is important to consider the difference in sensitivity between the
RT-PCR assays optimized for detection and follow-up of residual
leukemia in patients' specimens and the assay designed for the present
study. In the p210 and p190 RT-PCR protocols used in our laboratory for the analysis of clinical samples,17 the RNA content from
approximately 2.5 × 106 WBCs is analyzed by one
single PCR test. In contrast, the modified strategy we used for
screening normal individuals required the analysis of the whole RNA
content from 108 WBCs in 40 replicate PCR tests to score a
given sample as positive or negative. Because the sensitivity of the
two types of assays at the level of individual reactions is identical
(same amount of cDNA per reaction and same primers and reaction
conditions), the overall sensitivity of the modified assay can be
estimated as 40 times higher than that of the clinical protocol. On the basis of our results, the prevalence of BCR-ABL carrying leukocytes in
the blood of healthy individuals is probably around less than 1 to 10 in 108 WBCs, indicating that an average 70-kg normal adult,
with a mean blood volume of 5.6 L and 5 to 10 × 109 WBCs/L, may have around 300 to 6,000 circulating
leukocytes with a t(9;22) and possibly an unknown number in the bone
marrow. It is not known whether these BCR-ABL-positive cells arise
independently a large number of times in each individual or whether
they are part of a single clone that has undergone a considerable
although limited degree of expansion. If the latter, such a clone would have to double from 8 to 13 times to produce 256 to 8,192 cells, ie,
the range of t(9;22)-positive cells estimated to be present in the
circulation of healthy adults. This would imply that tests for residual
disease in patients' samples may have a 1 in 40 chance of being false
positive, ie, of detecting this low background of leukemia-unrelated
BCR-ABL-containing leukocytes. Such a low rate of false positivity
would not be of practical significance, because the clinical value of
residual leukemia assessment relies on its pattern of evolution during
a sequential quantitative PCR analysis after treatment (bone marrow
transplantation and -interferon), rather than on isolated
qualitative PCR test results.24,25 Even for patients
monitored by qualitative RT-PCR assays after allogeneic bone marrow
transplantation, the minimum criterion for therapeutic intervention in
the form of donor lymphocyte infusions is the finding of two sequential
positive tests.26 The chance of two consecutive false
positive assays occurring would be 1/40 × 1/40 = 1/1,600, a
probability too low to be of any practical concern. However, it is
possible that the chance detection of nonmalignant BCR-ABL-positive
leukocytes may underlie the phenomenon of apparent transient or
intermittent molecular relapse observed in some CML patients who remain
in clinical remission after bone marrow
transplantation.27,28
| |
FOOTNOTES |
Submitted January 24, 1998;
accepted June 11, 1998.
Supported in part by grants from the Leukaemia Research Fund (UK) and
the Dr Mildred Scheel-Stiftung fur Krebsforshung (Germany).
Address reprint requests to Junia V. Melo, MD, PhD, Department of
Haematology-ICSTM, Hammersmith Hospital, Ducane Road, London W12 0NN,
UK; e-mail: jmelo{at}rpms.ac.uk.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract