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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1381-1389
The t(6;8)(q27;p11) Translocation in a Stem Cell Myeloproliferative
Disorder Fuses a Novel Gene, FOP, to Fibroblast Growth
Factor Receptor 1
By
Cornel Popovici,
Bin Zhang,
Marie-José Grégoire,
Philippe Jonveaux,
Marina Lafage-Pochitaloff,
Daniel Birnbaum, and
Marie-Josèphe Pébusque
From the Laboratoire d'Oncologie Moléculaire, U.119 INSERM,
Institut de Cancérologie et d'Immunologie de Marseille,
Marseille, France; the Laboratoire de Biologie des Tumeurs, Institut
Paoli-Calmettes (IPC), Marseille, France; the Laboratoire de
Génétique, Centre Hospitalier Universitaire, Nancy, France;
and the Laboratoire de Cytogénétique, Département
d'Hématologie, IPC, Marseille, France.
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ABSTRACT |
In patients with an atypical stem-cell myeloproliferative disorder
with lymphoma (B or T cell), myeloid hyperplasia, and eosinophilia, the
chromosome 8p11-12 region is the site of a recurrent breakpoint that
can be associated with three different partners, 6q27, 9q32-34, and
13q12. Rearrangements are supposed to affect a pluripotent stem cell
capable of myeloid and lymphoid differentiation and to involve the same
8p11-12 gene. The t(8;13) translocation has recently been shown to
result in a fusion between the FGFR1 gene that encodes a
tyrosine kinase receptor for fibroblast growth factors and a novel
gene, FIM (also called RAMP or ZNF198),
belonging to a novel family of zinc finger genes. In the present study, we have cloned the t(6;8)(q27;p11) translocation in two patients and
found a fusion between FGFR1 and a novel gene, FOP
(FGFR1 Oncogene Partner), located
on chromosome band 6q27. This gene is alternatively spliced and
ubiquitously expressed. It encodes a protein containing two regions of
putative leucine-rich repeats putatively folding in  -helices and
separated by a hydrophobic spacer. The two reciprocal fusion
transcripts were evidenced by reverse transcription-polymerase chain
reaction in the tumoral cells of the patients. The
predicted chimeric FOP-FGFR1 protein contains the FOP N-terminus
leucine-rich region fused to the catalytic domain of FGFR1. It may
promote hematopoietic stem cell proliferation and leukemogenesis
through a constitutive phosphorylation and activation of the downstream
pathway of FGFR1.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
SPECIFIC RECURRENT chromosomal
translocations have been described for many malignant tumors, including
leukemias, lymphomas, and sarcomas.1 Characterization of
translocation breakpoints has shown fusion of genes frequently encoding
potential transcription factors and nucleic acid-binding proteins or,
in some instances, tyrosine kinases,2 which lead to the
generation of chimeric products and/or alteration of gene
expression, thereby providing a putative oncogenic
stimulus.3-5
A recently described distinct myeloproliferative disorder (MPD) is
associated with recurrent translocations in which the 8p11-12 chromosomal region is rearranged with three different partners, 6q27,
9q32-34, and 13q12.6 This hematological malignancy is characterized by myeloid hyperplasia, eosinophilia, and T- or B-cell
lymphoblastic lymphoma and generally progresses to acute myeloid
leukemia (AML). The biphenotypic feature of this MPD strongly suggests
that the genetic abnormality occurs in the hematopoietic stem cell. The
8p11-12 breakpoint has been recently characterized.7,8 It
is distinct from the breakpoints in other translocations evidenced in
AML, ie, t(8;16)(p11;p13)9 and its
t(8;14)(p11;q11.1),10 and t(8;19)(p11;q13)11
variants and t(8;22)(p11;q13).12,13 The MOZ gene is
involved in the t(8;16) translocation14 and in AML with
inv(8)(p11;q13).15 We have demonstrated that the three
different translocations associated with MPD have the same localization
of the 8p11-12 breakpoint and that cosmids specific of the fibroblast
growth factor receptor 1 (FGFR1) gene spanned the
breakpoint.16 FGFR1 encodes a receptor for members
of the fibroblast growth factor family.17 Four groups at
least have cloned the t(8;13) breakpoint. All studies showed that this
translocation results in the fusion of the FGFR1 gene to a
previously unidentified 13q12 gene named FIM,18
RAMP,19 or ZNF198.20,21 The
putative oncogenic fusion protein contains zinc finger motifs,
contributed by the product of the 13q12 gene, and the catalytic domain
of FGFR1.18-22 The chimeric protein is relocalized to the
cytoplasm20 and has a constitutive tyrosine kinase
activity.18 These findings strongly suggest that the
genesis of the 8p11-12 MPD syndrome is due to altered FGFR1 signal
transduction pathways.
Among the rearrangements specific of the 8p11-12 MPD, the
t(6;8)(q27;p11) is a rare recurrent translocation and, to date, only
four cases have been described.16,23,24 In the present study, we report that FGFR1 is fused to a novel gene we named FOP (FGFR1 Oncogene
Partner) in two patients. In both cases, the translocation
results in the fusion of a putative leucine-rich domain of FOP to the
protein kinase domain of FGFR1. The two reciprocal fusion transcripts
are expressed. The t(6;8) breakpoint occurs within FGFR1 intron
8, as is the case for the t(8;13) translocation.18
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MATERIALS AND METHODS |
Patients.
The two patients with a t(6;8)(q27;p11) studied have been partially
described in a previous work.16 The clinical phenotype in
each case was consistent with the 8p11-12 MPD.6
Patient no. 1 was a 27-year-old man with a white blood cell count (WBC)
of 62 × 109/L with 48% myeloid cells. The bone
marrow aspirate was extremely hypercellular, with, respectively, 10%
and 28% of eosinophilic and lymphoid cell population. A
46,XY,t(6;8)(q27;p11) karyotype was found in the 49 bone marrow-derived
metaphases studied. A 7-month treatment with hydroxyurea reduced the
WBC. Two years later, a polycythemia vera was diagnosed. Five years
later, the disease progressed to acute myeloid leukemia, and the
patient died 6 months later after incomplete remission.
Patient no. 2 was a 19-year-old man. When the patient was 12 years of
age, a polycythemia vera associated with a cutaneo-mucous lichen was
diagnosed. Complete hematological remission was obtained after
treatment with hydroxyurea, but the skin disorder was unresponsive to
the immunosuppressive treatment. When the patient was 19 years of age,
the number of polymorphonuclear neutrophils increased to 20 × 109/L. Bone marrow examination evidenced hyperplasia in the
three myeloid lineages without fibrosis or eosinophilia. At that time, chest x-rays showed enlargement of thymus and histological examination after exeresis showed lymphoid hyperplasia. One year later, cervical and axillary lymphadenopathies appeared and histological examination displayed infiltration by myeloid blast cells. Acute transformation into AML4 with 40% blasts in bone marrow was diagnosed. Bone marrow karyotype showed a t(6;8)(q27;p11) in the 32 mitoses analyzed. After
high-dose chemotherapy, a return to chronic phase was obtained. Nine
months later, a Lyell syndrome was diagnosed and the patient died from
septic shock.
Human cell lines.
The following cell lines were cultured as recommended by the supplier:
IE8, pre-B/B stage acute lymphoblastic leukemia (ALL); JY,
B-ALL; U937, histiocytic lymphoma; KG1, myeloblastic/promyelocytic AML;
SU-DHL-1, Ki-1 lymphoma cells bearing a t(2;5)(p23;q35); Daudi,
Burkitt's lymphoma; HSB-2, MO, and MOLT-4, T-ALL; HEL, erythroleukemia
AML; HL60, promyelocytic AML treated or not with phorbol esters; MIA
PaCa-2, pancreas carcinoma; IMR-90, lung fibroblast; A549, lung carcinoma.
All cell lines were purchased from the American Type Culture Collection
(ATCC; Rockville, MD), except for IE8 (gift from T. LeBien, Medical School, University of Minnesota, Minneapolis, MN) and SU-DHL-1 (gift from R. Rimokh, Hôpital E. Herriot, Lyon, France).
Fractionation of peripheral blood cells.
Peripheral blood cells were isolated from blood samples obtained from
healthy donors (Centre Régional de Transfusion Sanguine, Marseille, France) and fractionated in the four major hematopoietic nucleated populations (B and T lymphocytes, granulocytes, and monocytes) as previously described.25 The percentage of
purified normal cells was more than 90%, as assessed by
immunophenotype analysis.
cDNA cloning and sequencing.
The fusion transcript was analyzed with a Marathon cDNA amplification
kit (Clontech, Palo Alto, CA). First-strand cDNA was synthesized from 2 µg of t(6;8) total RNA (case no. 1) by using an
FGFR1-specific antisense primer (F5R,
5'-ATGGACAGGTCCAGGTACTCC-3'). Second-strand cDNA was
synthesized and adapter ligated according to the manufacturer's
protocol. The fusion transcript was amplified with an
FGFR1-specific antisense primer (F-4R,
5'-ACTCTGGTGGGTGTAGATCCG-3') and adapter primer AP1 from
the Marathon kit. Polymerase chain reaction (PCR)
conditions were as follows: initial denaturation at 95°C for 5 minutes, then 95°C for 1 minute, 60°C for 1 minute, and
68°C for 4 minutes for 30 cycles, with a final elongation step at
68°C for 10 minutes. One tenth of the first-round PCR product was
reamplified with a nested-specific FGFR1-specific antisense
primer (F-3R, 5'-CTTGGAGGCATACTCCACGAT-3') and adapter primer AP2. PCR conditions were the same as for the first-round amplification. The second-round PCR product was precipitated in ethanol
and subcloned in the pUC18 vector by using the Sure Clone Ligation kit
(Pharmacia, Uppsala, Sweden). Nucleotide sequences were
obtained using the T7Sequencing kit (Pharmacia) and the
forward and reverse sequencing primers for pUC18. Products were
analyzed on 5% polyacrylamide/urea sequencing gels.
The full-length FOP cDNA was obtained by screening the SCID
t(8;13) library we previously constructed.18 Approximately
106 plaque-forming units were screened with a 1.5-kb
Not I-EcoRI fragment from cDNA clone zs55g02. Clone
sequencing was performed as described above or at Génome Express
(Grenoble, France) on an automated sequencer (Applied Biosystems 373;
Applied Biosystems, Foster City, CA). Comparisons with
GenBank and dbEST entries were made using BLASTN and
TBLASTN.26 Comparisons with protein databases (EMBL;
Swissprot, Geneva, Switzerland) used BLASTX,
TBLASTX.27 Protein alignment was performed using multiple
sequence alignment software28
(http://www.toulouse.inra.fr/multalin.html).
Northern blot analyses.
The multiple tissue Northern blots (Clontech; no. 7759-1, 7760-1, and
7767-1) were hybridized according to the manufacturer's instructions
by using, as a probe, the 1.5-kb Not I-EcoRI fragment from cDNA clone zs55g02 labeled with [32P]dCTP in random
priming reaction.
Determination of the genomic structure of FOP.
The genomic structure of the gene was deduced based on the cDNA
sequences of FOP, ESTs retrieved from dbEST database
(http://www.ncbi.nlm.nih.gov/irx/dbST/dbest_query.html), and the
genomic sequence from Pl artificial chromosome (PAC) 167A14 (accession
no. Z94721). Sequence comparisons were performed using
TBLASTN.26 Intron position was deduced from the
determination of both 5' and 3' limits of the
exons.29
For alternative splicing analysis, reverse transcription-PCR (RT-PCR)
experiments were performed. Three primer sets from the 5' end
(sense, 5'-GGAGCGTACCCTGCTGCG-3'; antisense,
5'-CCTTCGAGACCTTGCAGC-3'), middle part (sense,
5'-TTAGTGGCTAGTCTTGTTGC-3'; antisense,
5'-TAAAGAAGGGGCTCCCGC-3'), and 3' end (sense,
5'-GAAGCAAGCAGGAAGTCTGG-3'; antisense,
5'-GCAGTGTTTTTGAAATGCAAGG-3') of FOP sequence were
used to amplify FOP transcripts. PCR reactions were performed
in a Perkin Elmer-Cetus (Norwalk, CT) apparatus using an
equivalent of 500 ng of reversed transcribed RNA and 50 pmol of each
oligonucleotide as primers. The first cycle was run as follows:
denaturation at 95°C for 5 minutes, annealing at 60°C for 30 seconds, and synthesis at 72°C for 1 minute. The next 30 cycles
were run using the same conditions except that the denaturation step
was only 30 seconds. For the last cycle, the synthesis time was 7 minutes. PCR products were gel-purified in agarose 1%, subcloned and
sequenced as described above.
Analysis of gene expression by RT-PCR.
RT-PCR reactions were performed from 2 µg of total RNAs as previously
described.18 Fusion transcripts were analyzed for the two
t(6;8) patients. FOP-FGFR1 fusion transcript was
amplified with the FOP-specific sense (FOP-1F,
5'-CATTCTCCACCAAAGTCACCA-3') and FGFR1-specific
antisense (F-9.2, 5'-CATACTCAGAGACCCCTGCTAGC-3') primers,
giving a 162-bp product. FGFR1-FOP fusion transcript was amplified with FGFR1-specific sense (FA,
5'-ATCATCTATTGCACAGGGGCC-3') and FOP-specific
antisense (FOP-1R, 5'-CCCGCTTGTCTTCTTCTTACC-3') primers
that generated a 197-bp product. PCR conditions were as described above.
The wild-type FOP and FGFR1 transcripts were amplified
using FOP-1F/FOP-1R (PCR product of 101 bp) and FA/F-9.2 (PCR product of 258 bp) primer pairs, respectively. PCR conditions were as described above.
The human  2 microglobulin primer pair (sense,
5'-CCAGCAGAGAATGGAAAGTC-3'; antisense,
5'-GATGCTGCTTACATGTCTCG-3'; PCR product of 268 bp) was used
as a control for RT and PCR efficiency.
| |
RESULTS |
Cloning of the MPD t(6;8) breakpoint.
To clone the putative fusion gene, we did PCR amplification of cDNA
5' ends (5'-RACE) from t(6;8) malignant cell total RNA (case 1) by using FGFR1-specific oligonucleotides. The
resulting PCR products were cloned. Two chimeric clones of 400 and 800 bp were sequenced, showing that a sequence not previously characterized was fused in a continuous reading frame to FGFR1 at nucleotide 1272 from ATG (accession no. M34185). Database searches with the novel
sequence showed identity with human DNA sequences from one PAC, PAC
167A14 (EMBL Z94721) localized on chromosome 6q27, but did not show
significant similarity or identity to any known gene or protein. We
named this novel gene FOP. ESTs were shown to correspond to PAC
167A14 and we studied some of these cDNA clones. Sequencing of cDNA
clone zs55g02 from which two ESTs (AA286845 and AA286846) are available
in dbEST showed that it contained the sequences surrounding the
breakpoint identified in PCR products from patient RNA.
Cloning of FOP gene.
A cDNA library we previously constructed18 was screened
with the insert from cDNA clone zs55g02 as a probe. Two of the largest clones isolated were sequenced. They all shared identical sequences with ESTs AA286845 and AA286846, one of which had a 5' extended end of 150 bp and was approximately 1.7 kb in length. The cDNA and
deduced aminoacid sequences of FOP are shown in
Fig 1. Within the full-length cDNA of 1,630 bp (EMBL: Y18046), a single open reading frame of 1,197 nucleotides
starts with the putative ATG at nt 85. The sequence surrounding this
codon matches the consensus sequence for optimal translation
initiation, as determined by NetStart 1.0, a program for translation
start prediction (http://www.cbs.dtu.dk/services/NetStart/). A stop
codon at nt 1,282 is followed by a 338-bp long 3' untranslated sequence, including a polyadenylation signal upstream to a poly(A) tail. It encodes a putative protein of 399 amino acid residues (aa).
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| Fig 1.
Sequences of the human FOP gene. A full-length
FOP cDNA clone is shown with the predicted amino acid sequence
of an open reading frame. Leucine residues that may correspond to a
novel type of leucine-rich motifs are in bold. Putative -helices are
underlined. Arrowheads indicate exon/intron boundaries. The arrow
corresponds to the t(6;8) breakpoint. The asterisk indicates the stop
codon.
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The genomic structure of FOP was deduced based on the cDNA
sequences, ESTs retrieved from dbEST, and the genomic sequence from PAC
167A14. It is composed of 13 exons spanning more than 40 kb of genomic
DNA. The size of the exons is highly homogeneous, whereas the size of
introns is heterogeneous, ranging from 0.5 to 8.8 kb
(Fig 2A). All of the intron/exon boundaries
agree with the canonic acceptor and donor splice sites.29
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| Fig 2.
(A) Schematic representation of the genomic structure of
the FOP gene. All exons are represented in the 5' to
3' order of genomic DNA: shaded and solid boxes represent
constant and alternatively spliced exons, respectively. Arabic and
roman numbers indicate the size in kilobases of introns and the
position of exons, respectively. The arrow indicates the breakpoint.
Restriction enzyme sites are BamHI (B), EcoRI (E), and
Xba I (X). (B) Similarities of the deduced human FOP protein
(Hs) with EST protein translation from Mus musculus (Mm),
Danio rerio (Dr), Leishmania major (Lm), and
Oryza sativa (Os). Shading indicates common (boxed) and similar
amino acid residues. Numbers at the top of each alignment indicate
amino acid positions in FOP. Asterisks show conserved leucine
residues.
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Multiple FOP cDNA variants were identified as the result of
alternative splicing. In some cDNA clones an additional exon, exon 11 (Fig 2A), was identified. Variant transcripts resulting from splices of
either exon 7 or exon 11 were cloned by RT-PCR and also found in
several human and murine ESTs (including AA919880) and a human EST
(N46560), respectively. It must be pointed out that, when exon 11 is
not spliced out, a shorter protein of 331 aa can be deduced as the
result of the presence of an in-frame stop codon. Moreover, an
alternative splice is suspected in the FOP 3' noncoding part.
FOP sequence motifs.
Analysis of the transcript containing 1,197-bp FOP coding
sequence suggests that FOP encodes a protein of 399 amino acid
residues with a predicted molecular mass of 44.3 kD. FOP is a protein
largely hydrophilic and contains, in its N- and C-termini, several
regions folding in  -helices, as determined using GOR secondary
structure prediction program.30 These two regions are
interrupted by a hydrophobic spacer region (Fig 1). The -helix
regions contain repeats with the consensus sequence
L-X2-L-X3-5-L-X3-5-L, in one-third of which the leucine is substituted by either a valine or an isoleucine.
Evidence for a novel gene family.
The EST database (NCBI, Bethesda, MD) was screened for
sequences similar to the FOP gene. Several human ESTs, whose
deduced amino acid sequence (after translation in the 6 reading frames) has similarities to portions of the FOP protein, were found. These results are evidence for a multigenic family. EST similarities were
found not only in vertebrates including human, mouse (AA103209, AA919880), and zebrafish (AA497344), but also in more distant phyla
such as monocellular eucaryotes (leishmania, AI034687) and plants
(rice, RICS1091A). The alignment of the deduced N-terminus of the FOP
protein with translated nonhuman ESTs displaying sequence similarities
and encoding putative orthologs is shown in Fig 2B.
Gene expression.
Expression of the wild-type FOP gene was investigated by
Northern blot analysis of poly(A)+ RNAs of various human tissues. Two
major transcripts of approximately 1.2 and 1.7 kb were detected in all
samples (Fig 3). A high level of expression
and an additional transcript of approximately 3 kb were detected in the
heart. Using RT-PCR analysis, FOP expression was found in
normal hematopoietic cells as well as in different malignant cell lines
(Fig 4). Similarly, FGFR1
expression was found in normal and tumoral cells (Fig 4), in agreement
with previous studies.18,31,32 FOP and
FGFR1 were expressed in the two t(6;8) patients' samples
(Fig 5, rows 1 and 4 in the middle and
right panels, respectively).
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| Fig 3.
FOP expression. Clontech Northern blots with the
indicated poly(A)+ RNAs were hybridized with an
FOP probe derived from cDNA insert of clone zs55g02. -Actin
was used as a control. The marker sizes (in kilobases) are indicated on
the left.
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| Fig 4.
Expression of FGFR1 and FOP genes. RT-PCR
products were obtained from a variety of tissues and normal and tumoral
hematopoietic cells using specific primer pairs of each gene. Each
panel is a photograph of the ethidium bromide-stained agarose gel in
which PCR products were electrophoresed. Labels at the top of rows
indicate the source of the material. The first row corresponds to cDNA
controls: a 2.5-kb FGFR1 cDNA (pFLG-16) containing the complete
coding sequence (upper panel)49 and the FOP cDNA
clone zs55g02 (middle panel), respectively. The other rows correspond
to RNAs from a variety of lympho-hematopoietic cell lines (listed in
Materials and Methods) and mature peripheral (T lymphocytes, B
lymphocytes, and monocytes) blood cells purified as indicated in
Materials and Methods. 2 microglobulin (2M) amplification
was used as a control.
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| Fig 5.
Expression of the fusion transcripts. RT-PCR were
performed using RNAs from the erythroleukemia HEL cell line used as a
control (left panel) and from the two t(6;8) patients' malignant cell
samples and specific primers located near the translocation breakpoint.
The respective chromosomal positions and the transcripts identified in
each reaction are indicated at the top and on the right,
respectively.
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Predicting the transcription of chimeric messages over the breakpoint,
we designed primers from FOP and FGFR1 to do RT-PCR on
RNA from the two t(6;8) patients. Both FGFR1-FOP and
FOP-FGFR1 reciprocal transcripts were detected in
patients (Fig 5, rows 2 and 3 in the middle and right panels,
respectively) but not in normal and other tumoral samples (Fig 5, left
panel, rows 2 and 3, respectively). They proved to encode in-frame
fusion junctions on sequence analysis (Fig
6).
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| Fig 6.
Schematic representation of FGFR1, FOP, and both
FOP-FGFR1 and FGFR1-FOP fusion proteins. FGFR1 domains are indicated as
follows: IgI, IgII, and IgIII, the three Ig-like domains; TM, the
transmembrane domain; and TK1 and TK2, the tyrosine kinase 1 and 2 subdomains interrupted by a kinase insert (KI). Waved lines in the N-
and C-terminal parts of FOP represent the leucine-rich repeats.
FGFR1-FOP retains the extracellular and transmembrane domains of FGFR1,
whereas FOP-FGFR1 fusion protein contains the FGFR1 catalytic domain.
Double arrows indicate the t(6;8) breakpoint. Nucleotide and amino acid
breakpoint sequences are indicated for both resultant chimeric
products.
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Characterization of the fusion junctions.
We next determined the nucleotide sequence spanning the breakpoints on
both parental and translocated chromosomes. On chromosome 8, the break
occurred in FGFR1 intron 8, 139 bp upstream of exon 9, which
encodes the intracellular juxtamembrane domain. Two variants of the
FGFR1-FOP fusion transcribed from chromosome
der(8) were obtained. They differ by the use of alternative
FGFR1 5' splice sites located six nucleotides apart at
the 3' end of exon 8. They lead to inclusion or not of two amino
acids, VT (Fig 3), in the juxtamembrane region, a feature described for
wild-type FGFR1,33,34 and in the fusion product resulting
from the t(8;13) translocation.18 On chromosome 6, the
break occurred in FOP intron 6, 424 bp downstream of exon 6. FOP intron 6 is 2.6-kb long and contains two AT rich regions, a
CA(n) repeat region and a subtype of long terminal repeat (LTR/MaLR),
located downstream of the breakpoint. The chimeric sequence
5'-ATGGTCTTT-3' of the rearranged intron from the
FOP-FGFR1 fusion gene results from the sequences
5'-ATGGTTTTT-3' and 5'-ATGGTCTTT-3' of
FOP intron 6 and FGFR1 intron 8, respectively. It is
noteworthy that the breakpoint occurs in an identical stretch of
nucleotides (but for one) in both FOP and FGFR1
wild-type introns. The characteristics of the wild-type FGFR1 and FOP
proteins, the fusion proteins FOP-FGFR1 and FGFR1-FOP, are depicted in
Fig 6.
| |
DISCUSSION |
In this study, we describe the fusion of the FGFR1 gene with a
previously uncharacterized gene, FOP, in the t(6;8)
translocation involved in the myeloproliferative syndrome linked to the
8p11-12 chromosomal region. Two novel leukemia-specific fusion genes, FGFR1-FOP and FOP-FGFR1, were
identified as the result of the translocation. In contrast to many
chromosome translocations, both chimeric gene derivatives are expressed
in patient cells. This observation is consistent with two works in
which the expression of both FIM-FGFR1 and
FGFR1-FIM RNAs in cells with t(8;13) associated with
the same syndrome.18,22 In both t(8;13) and t(6;8)
translocations, the breakpoints in the FGFR1 gene lie in intron 8.
To date, two of the three chromosomal translocations consistently
associated with myeloproliferative disorder linked to the 8p11-12
chromosomal region have been cloned. The FGFR1 partners are
unrelated novel genes. Our preliminary results from the molecular study
of the t(8;9) translocation demonstrate that the 9q32-34 gene is also a
novel gene that is different from the two others (Popovici et al,
manuscript in preparation). In each fusion, the N-terminal region of the novel proteins, postulated to trigger protein
dimerization, is fused to the catalytic domain of FGFR1. In the
t(8;13), the 13q12 gene encodes a member of a novel family of zinc
finger proteins.18-21 In the present work, we show that the
t(6;8) translocation is associated with a leukemic aberrant protein in
which a putative leucine-rich N-terminal region encoded by the widely
expressed chromosome 6 FOP gene. Indeed, FOP encodes a
protein that has, in its N- and C-terminal parts, some structural features involving putative -helices. The comparison of aligned internal FOP sequences show considerable conservation of
leucines that may correspond to a novel type of leucine-rich repeats.
Because these motifs are different from the consensus leucine-rich
repeats present in a large family of proteins involved in various
functions and found in a great variety of species,35,36 we
postulate that FOP may define a novel family of leucine-rich proteins.
In addition, we retrieved from databases several ESTs with sequence similarities from humans and from distant phyla. Altogether, these results suggest that FOP belongs to a multigenic family and is highly conserved during evolution.
To date, proteins containing leucine-rich repeats are thought to be
involved in protein-protein interactions, and at least half of them
take part in signal transduction.35 We previously showed
that the putative oncogenic fusion gene involved in the t(8;13)
translocation has a constitutive tyrosine kinase
activity.18 Thus, the oncogenic role of the
FOP-FGFR1 fusion gene product may be mediated by constitutive
phosphorylation of the FGFR1 kinase domain triggered by dimerization of
FOP leucine-rich motif.
Distinct species of human FOP cDNAs derived from differential
splicing were identified. This raises the possibility that, although
the FOP gene is expressed ubiquitously in various tissues and
organs, the expression of its alternative splicing products may be
regulated in a tissue-specific fashion.
The FGFR1 gene encodes a tyrosine kinase receptor for members
of the fibroblast growth factor family.17 FGFR1 is one of the four FGF receptors responsible for mediating cellular responses to
fibroblast growth factor signaling, which include mitogenesis, mesoderm
induction, angiogenesis, chemotaxis, and neuronal
survival.37,38 Signals from FGFRs appear to control
differentiation as well as proliferation. FGFR1 is specifically
involved in a hereditary craniosynostosis syndrome39 and
may contribute to tumorigenesis in human cancers. FGFR2 constitutive
activation after chromosomal rearrangement was shown in rat
osteosarcoma cells.40 Activating mutations
associated with translocation involving FGFR3 and the IgH locus
were described in some cases of multiple myeloma.41 FGFR1 may be the key gene for driving the 8p11 amplification
process in breast cancers.42-45 Its likely oncogenic role
in the 8p11-12 MPD has been documented in previous
works16,18-21 and is strengthened by this study. These data
therefore provide a new example of an oncogene implicated in both solid
tumor formation and leukemogenesis.
Our present data suggest not only that alteration of transcriptional
cascades mediated by FGFR1 signaling may be a mechanism of leukemic
transformation, but also that FGFR1 may play a role in normal
hematopoietic development. The finding of acquired chromosomal translocations that are consistently associated with specific tumor
types supports the hypothesis of lineage-specific mechanisms of
tumorigenesis.46 In the case of 8p11-12 MPD, the crucial event for transformation is likely to take place in the hematopoietic stem cell, as previously postulated,6 leading to the
disruption of normal hematopoiesis of both lymphoid and myeloid
lineages. Increased expression of FGF2 and its receptors has been
recently shown in CD34+ hematopoietic progenitors from
patients suffering from an MPD with myelofibrosis and myeloid
metaplasia.47 Molecular reagents derived from t(6;8) or
t(8;13) may be used to facilitate the expansion of stem cells by
stimulating their growth and/or survival and by overcoming
negative regulatory signals.
In MPD, proliferative activity in the bone marrow is seldom limited to
a single lineage, but often involves the erythroid, granulocytic,
and/or megakaryocytic series.48 It may be of
interest to note that, whereas overlapping clinical features are found in all patients with MPD linked to 8p11-12,6 a polycythemia vera was diagnosed in both patients with a t(6;8) translocation. This
suggests that the chromosome 6 gene, FOP, may be an important gene for normal proliferation and differentiation of the erythroid lineage. A better understanding of the molecular processes affected by
the fusion of the genes involved in such an MPD may shed light on the
role of FGFR1 and its multiple fusion partners in
leukemogenesis and on the biology of the normal hematopoietic stem cell.
| |
ACKNOWLEDGMENT |
The authors thank Drs C. Mawas and D. Maraninchi for encouragement and
comments. We are grateful to Drs F. Birg, V. Ollendorff, and P. Pontarotti for helpful discussions. Thanks are also due to J. Adélaïde for occasional technical help and J. Simonetti for patient no. 2 karyotype.
| |
FOOTNOTES |
Submitted August 10, 1998; accepted October 12, 1998.
Supported by INSERM, Institut Paoli-Calmettes, and grants from the
Ligue Nationale contre le Cancer, Comité du Var de la Ligue
Nationale contre le Cancer, and FEGEFLUC. C.P. and B.Z. were recipients
of a fellowship from the Société Française d'Hématologie and People's Republic of China, 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 Marie-Josèphe Pébusque,
PhD, Institut de Cancérologie et d'Immunologie de
Marseille, Laboratoire d'Oncologie Moléculaire, INSERM U119, 27 Bd Leï Roure, 13009 Marseille, France; e-mail:
pebusque{at}marseille.inserm.fr.
| |
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Top
Abstract
Introduction