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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4370-4373
The Tyrosine Kinase Abl-Related Gene ARG Is Fused to
ETV6 in an AML-M4Eo Patient With a t(1;12)(q25;p13):
Molecular Cloning of Both Reciprocal Transcripts
By
Giovanni Cazzaniga,
Sabrina Tosi,
Alessandra Aloisi,
Giovanni Giudici,
Maria Daniotti,
Pietro Pioltelli,
Lyndal Kearney, and
Andrea Biondi
From the Clinica Pediatrica Università di Milano-Bicocca,
Ospedale San Gerardo, Monza, Italy; the MRC, Molecular Haematology
Unit, Institute of Molecular Medicine, Oxford, UK; and the Dipartimento
di Ematologia, Ospedale San Gerardo, Monza, Italy.
 |
ABSTRACT |
The Ets variant gene 6 (ETV6/TEL) gene is rearranged in the
majority of patients with 12p13 translocations fused to a number of
different partners. We present here a case of acute myeloid leukemia M4
with eosinophilia (AML-M4Eo) positive for the CBFb/MYH11 rearrangement
and carrying a t(1;12)(q25;p13) that involves the ETV6 gene at
12p13. By 3'rapid amplification of cDNA ends-polymerase chain reaction
(3'RACE-PCR), a novel fusion transcript was
identified between the ETV6 and the Abelson-related gene
(ARG) at 1q25, resulting in a chimeric protein consisting of
the HLH oligomerization domain of ETV6 and the SH2, SH3, and
protein tyrosine kinase (PTK) domains of ARG. The reciprocal
transcript ARG-ETV6 was also detected in the patient RNA by
reverse transcriptase-polymerase chain reaction (RT-PCR), although at a
lower expression level. The ARG gene encodes for a nonreceptor
tyrosine kinase characterized by high homology with c-Abl in
the TK, SH2, and SH3 domains. This is the first report on ARG
involvement in a human malignancy.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THE SHORT ARM OF chromosome 12 (12p) is a
region commonly involved in a wide variety of hematological
malignancies in both children and adult patients.1 The
ETV6/TEL gene was cloned by virtue of the translocation
t(5;12)(q33;p13) in the leukemic cells of a patient with chronic
myelomonocytic leukemia (CMML).2 More recently,
ETV6 has been shown to be rearranged in the majority of
patients with 12p13 translocations3,4 and fused to a number
of different partners (reviewed in Rubnitz et al5; see also
other studies6-9). Two possible mechanisms of
transformation have been proposed for ETV6/TEL fusion genes. First, aberrant transcription factors can result from joining the
3' region of ETV6 (Ets-family DNA binding domain) to the
5' region of the partner gene (reviewed in Rubnitz et
al5). Second, constitutive kinase phosphorylation, by
dimerization of protein tyrosine kinases, can result from joining of
the 5' region (HLH domain) of ETV6 to the 3' region
of the partner gene (reviewed in Rubnitz et al5). In fact,
the ETV6 gene has been previously reported to form fusion
transcripts with several tyrosine kinase genes.2,6-10 In
particular, ETV6 was found to be fused to Abl in some
rare acute lymphocytic leukemia (ALL),11 acute myeloid leukemia (AML),6 and chronic myeloid leukemia
(CML)12 cases.
We report here the identification of the Abelson-related gene
ARG as a fusion partner of ETV6 in a t(1;12)(q25;p13)
found in the leukemic cells of an adult patient with AML M4 with
eosinophilia and inv(16). This is the first demonstration of
ARG involvement in a translocation in a human malignancy.
| |
MATERIALS AND METHODS |
Patient.
The patient was a 54-year-old woman presenting the following laboratory
features: red blood cell count, 3.54 × 109/L; white
blood cell count, 116 × 109/L (with 6% lymphocytes
and 94% blasts); hemoglobin, 11.5 g/dL; and platelets, 36 × 109/L in peripheral blood. Diagnosis of AML was performed
by morphology: 45% myeloblasts, 22% monoblasts, 30% eosinophils, and
3% plasma cells were detected. Thus, the patient was classified as
AML-M4 with eosinophilia, according to the French-American-British
(FAB) classification. The presence of type A inv(16), undetectable by conventional cytogenetics, was demonstrated by reverse
transcriptase-polymerase chain reaction (RT-PCR)13 (data
not shown). At the end of the induction therapy, the patient achieved
complete hematological remission (CR). Six months later, she suffered
from bone marrow (BM) relapse, with 60% blast invasion of the BM. CR
was obtained after 2 courses of salvage therapy, but 4 months later,
the patient suffered a second BM relapse and central nervous system
involvement and died 4 months later from progression of disease.
Fluorescence in situ hybridization (FISH).
Probes used for FISH were as follows: (1) YAC 964c10, containing the
entire ETV6 gene (CEPH, Paris, France); and (2) cosmids from
the ETV6 gene14: 2G8 (exons 3 and 4) and 148B6
(exon 8; kindly provided by Dr P. Marynen, Centre for
Human Genetics, University of Leuven, Leuven, Belgium). FISH analysis
was performed on BM metaphases from archival methanol:acetic acid-fixed
chromosome suspension stored at  20°C as previously
described.6
PCR.
First-strand cDNA was reverse transcribed from 1 µg of total RNA with
Superscript II reverse transcriptase (GIBCO-BRL, Life Technologies,
Milano, Italy), according to standard procedures, using
the already described primer R2N6.7 Nested 3'rapid
amplification of cDNA ends-polymerase chain reaction
(3'-RACE-PCR) was performed using primers specific
for ETV6 exon 5 in combination with primers R2N6R1 and
R2N6R2,7 respectively. In
particular, the ETV6 primers designed for t(12;21) detection were
used.13 Colonies with recombinant plasmids containing the
PCR products were screened by hybridization using standard protocols.
Two oligonucleotide probes specific for both ETV6 exon 5 and
exon 6 were used. Clones positive for the exon 5 probe and negative for
the exon 6 probe were selected. These colonies were further screened by
RT-PCR using the ETV6 forward primer T-9
(5'-TGAAGAGCACGCCATGCCCATTG-3') and the
R2N6R2 as a reverse primer.
To confirm the presence of the ETV6-ARG fusion product,
RT-PCR was performed on patient RNA using standard procedures, with the
TA-4 forward primer (5'-ATCGGGAAGACCTGGCTTACA-3') on
ETV6 exon 5 and the TA-5 reverse primer
(5'-TGCCTGGGGTTCAACATCAC-3') on ARG. To detect the
reciprocal ARG-ETV6 transcript, first PCR was performed
using AT-10 forward primer (5'-GGAGCCGAGGAGGAATGT-3'), specific for ARG, in combination with AT-11 reverse primer
(5'-TGATTTCATCTGGGGTTTTCA-3') on ETV6 exon 6. Nested PCR was performed using AT-8 forward primer (5'-GATGGGGCAGCAGGTG-3') on ARG in combination with
AT-9 reverse primer (5'-CAGGGCTCTGGACATTTTCTC-3') on
ETV6 exon 6.
| |
RESULTS AND DISCUSSION |
Cytogenetic analysis at diagnosis of a patient with AML-M4Eo showed the
presence of a t(1;12)(q25;p13) as the sole chromosomal abnormality
associated with the disease. However, using RT-PCR, we demonstrated
positivity for type A inv(16), which is frequently detected in AML-M4Eo
patients.15 FISH with the YAC 964c10, containing the entire
ETV6 gene,14 showed a fluorescent signal on both the der(12) and the der(1), indicating that the breakpoint on chromosome 12 was contained within this clone
(Fig 1). Further FISH analyses with cosmids
from the ETV6 gene confirmed that the breakpoint was within
ETV6, between cosmid 2g8 (exons 3 and 4) and 148b6 (exon 8)
(data not shown).
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| Fig 1.
FISH analysis of the ETV6 rearrangement. FISH
with the ETV6-containing YAC 964c10 to leukemic metaphases.
Arrows indicate fluorescent signals corresponding to YAC 964c10 on the
der(1) and the der(12); the arrowhead shows the normal chromosome 12 homologue. The G-banding on the chromosomes was obtained by inverting
the DAPI-counterstained image.
|
|
To identify the fusion partner of ETV6, we performed
3'-RACE analysis on RNA from the patient, using nested primers
located in ETV6 exon 5. The whole 3'RACE-PCR product was
cloned in pMOS vector, and 200 bacterial colonies were screened using
both an ETV6-exon 6 primer and an ETV6-exon 5 primer
(internal to the one used in nested PCR) as probes. Using double
screening, we could exclude the presence of the unrearranged
ETV6 allele (21 positive colonies with exon 6 probe) and
consider only colonies ETV6-exon 6 negative and
ETV6-exon 5 positive (n = 40). To exclude PCR artefacts, these
colonies were further screened by PCR using T-9 forward primer and R2
reverse primer; 29 of 40 colonies were positive. Thirteen of 29 plasmids were sequenced. Seven clones represented the normal
ETV6 allele, 2 sequences corresponded to ETV6 intron 5, and the remaining 4 clones were completely sequenced in both
directions. Sequence analysis of the 4 clones detected an unknown
sequence fused to the ETV6 exon 5 sequence. This sequence was
proven to be the Abl-related gene ARG cDNA by BLAST database searching (GenBank accession no. M35296). Two clones (no. 24 and 37)
extended from nt 362 of ARG to nt 466; the other 2 (no. 14 and
35) corresponded to ARG cDNA through to nt 815 (Fig 2C).
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| Fig 2.
Analysis of the chimeric proteins. RT-PCR analysis of
ETV6-ARG (A) and ARG-ETV6 (B) fusion
products. Total RNA from the patient (lane 1) and 2 different healthy
donor white blood cells (lanes 2 and 3) was used for RT-PCR with
primers located in the relevant exons of ETV6 and ARG
(see Materials and Methods). Marker sizes are indicated on the left.
(A) RT-PCR analysis of ETV6-ARG. Two specific bands of
194 and 131 bp, respectively, were detected. The different PCR products
are the result of an alternative splicing event in the ARG
gene, as shown in (C). (B) RT-PCR analysis of ARG-ETV6.
One specific band of 343 bp was detected. (C) Schematic representation
of ETV6 (top) and ARG(IB) (bottom) cDNAs, 3'RACE
clones (boxed), and predicted ETV6-ARG and
ARG-ETV6 fusion proteins. The vertical arrow indicates
the breakpoint. The alternatively spliced hypothetical ARG exon
is indicated. HLH, helix-loop-helix domain; ETS, ETS-family DNA binding
domain; SH3, SH3 domain; PTK, protein-tyrosine kinase domain; pro rich,
proline-rich domains. Full-length cDNAs from the ARG and
ETV6 genes are shown at the top and bottom, respectively. The 2 different types of 3'RACE-PCR clones are shown in the box. The
nested PCR primers are indicated as arrows at the extremities of the
RACE clones.
|
|
Sequence analysis showed a deduced 1466 amino acid open reading frame
for the full-length ETV6-ARG fusion, starting at the ETV6 first ATG and ending at the ARG TAG stop codon.
The predicted size of the protein encoded by this transcript
is 161 kD.
RT-PCR analysis on patient material was performed to confirm the fusion
transcript between the ETV6 and ARG mRNA. Two fragments were unexpectedly detected using forward primer on ETV6 exon 5 (TA-4) and reverse primer on ARG (TA-5) (Fig 2A). Sequence
analysis showed that the 2 bands represent 2 alternatively spliced
ETV6-ARG transcripts. The larger product results from the
junction of exon 5 of ETV6 (nt 1033) to nt 362 of ARG,
exactly as the 3'RACE clones do. The smaller product
spliced exon 5 of ETV6 to nt 425 of ARG. Interestingly,
a CAG triplet is present at the end of ETV6 exon 5 (nt
1031-1033) and also at the nt 422-424 of ARG, corresponding to
the very beginning of the region common to ARG(IA) and
(IB).16,17 The sequence of the lower band in the
RT-PCR experiment on the patient showed the absence of 1 of the 2 repeated CAG triplets expected as a result of the mRNA splicing. Both
splicing forms result in an open reading frame linking the HLH
oligomerization domain of ETV6 to the complete SH3, SH2, and
PTK domain of ARG. PROSITE analysis of the fusion proteins
showed that no additional domains were added by virtue of the new
generated region at the junction site. Moreover, the only difference
between the alternatively spliced forms consists of an additional
Casein Kinase II phosphorylation site in the larger version. Indeed,
the absence of a CAG triplet in the spliced form does not generate any
difference in the recognized domains.
Interestingly, the alternative spliced portion of ARG (nt.362-422),
which is responsible for the lower RT-PCR band, does not have any
homology with Abl.17 Thus, we can expect that this small
portion represents a single exon of ARG.
The arg protein is a nonreceptor tyrosine kinase characterized by high
homology with c-abl in the TK, SH2, and SH3 domains (95%).16,17 Moreover, the products of the human
ARG gene and human, mouse, Drosophila, and nematode Abl
genes are characterized by high homology, indicating that they can have
an important function conserved during the evolution. By contrast, the
variation in the N-terminal and C-terminal domains of arg and c-abl may
account for their different functions.17 In particular, arg
is cytoplasmic,18 but c-abl has both nuclear and
cytoplasmic localization.19 The abl and arg
products have also different transforming activity mediated by the
distinct arg and abl C-terminal domains (CTD).20 So far,
there is little information on the role of Arg in the cell;
moreover, the role of Arg in the hematological system is still unknown.
Receptor and nonreceptor tyrosine kinases are known to play an
important role in cell growth and differentiation. Amplifications, mutations, or recombinations involving these genes can result in
increased activation of their kinase domain, which leads to cellular
transformation. In both the ETV6-PDGFRb and ETV6-Abl fusion transcripts,21-23 it has been demonstrated that the
HLH domain contained in ETV6 confers the oncogenic activity to
the chimeric PTK proteins by forming HLH domain-dependent
homo-oligomers that result in ligand-independent tyrosine kinase
activation.21-23 ETV6-Abl, like BCR-Abl
[which is consistently observed in t(9;22)-positive CML or ALL],
leads to increased tyrosine kinase activity contained within the abl
part and relocalization of abl from the nucleus to the actin
cytoskeleton of the cytoplasm.22 Moreover, BCR-Abl and ETV6-Abl seem to activate similar signal transduction
pathways23 and show similar transforming
activity.22,23 In addition, it has been demonstrated that
the ETV6-Abl expression in factor-dependent murine
hematopoietic precursor cells transforms these cells, converting them
to factor independence for both survival and growth.24
Because of the tight homology between ARG and c-Abl and
the very similar activity of both etv6-abl and bcr-abl chimeric
proteins,22,23 the homodimerization property of the HLH
domain can also be proposed as an activation mechanism of the
etv6-arg chimeric protein kinase. However, further experiments
are needed to confirm this hypothesis.
In contrast to the t(5;12), t(12;15), and t(9;12), in which the
reciprocal transcripts ETV6-PDGFR, ETV6-TRKC, ETV6-ABL, and ETV6-JAK2 were not detected,2,7-12 we could demonstrate
the presence of reciprocal ARG-ETV6 transcript in the
t(1;12) (Fig 2B). However, the presence of the latter was detected only
by nested PCR, indicating that this transcript was expressed at a low
level in the patient leukemic cells. The reciprocal full-length ARG-ETV6 transcript accounts for a 168 amino acid open reading frame, starting at the ARG first ATG and ending at the
ETV6 TGA stop codon. This transcript consists of the fusion
between the NH2 region of ARG to the ETV6 exon 6, which
retains the Ets-DNA binding domain of ETV6 and results in a
hypothetical 20-kD protein. The presence of this protein and its role
in the leukemic cells have still to be fully investigated. However, it
is possible to speculate that the aberrant DNA-binding protein would
interact with the physiological ETV6 target genes, although
under the regulation of the Arg promoter.
In conclusion, this is the first demonstration of the involvement of
the Abelson-related gene ARG in a translocation in a human
hematologic malignancy. In future experiments, the analysis of the
chimeric proteins that arise from this translocation should elucidate
both the physiological and the aberrant role of ARG in
hematopoietic cells.
| |
FOOTNOTES |
Submitted July 6, 1999; accepted August 12, 1999.
Supported by Fondazione M. Tettamanti, Associazione Italiana per la
Ricerca sul Cancro (AIRC), MURST 40%. S.T. and L.K. are supported by
the Leukaemia Research Fund, UK, and the Medical Research Council, respectively.
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 Giovanni Cazzaniga, PhD,
Clinica Pediatrica Università di Milano-Bicocca, Centro Ricerca
Tettamanti, Nuovo Ospedale San Gerardo, Via Donizetti, 106, 20052 Monza, Italy; e-mail: fondazione.tettamanti{at}galactica.it.
| |
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F. Yagasaki, D. Wakao, Y. Yokoyama, Y. Uchida, I. Murohashi, H. Kayano, M. Taniwaki, A. Matsuda, and M. Bessho
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K. Okuda, E. Weisberg, D. G. Gilliland, and J. D. Griffin
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A. Buijs, L. van Rompaey, A. C. Molijn, J. N. Davis, A. C. O. Vertegaal, M. D. Potter, C. Adams, S. van Baal, E. C. Zwarthoff, M. F. Roussel, et al.
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M. W. N. Deininger, J. M. Goldman, and J. V. Melo
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C. Cao, X. Ren, S. Kharbanda, A. Koleske, K. V. S. Prasad, and D. Kufe
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M. H.-H. Nguyen, J. M.-Y. Ho, B. K. Beattie, and D. L. Barber
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TOP
ABSTRACT
INTRODUCTION