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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3265-3268
TRK-Fused Gene (TFG) Is a New Partner of ALK in
Anaplastic Large Cell Lymphoma Producing Two Structurally Different
TFG-ALK Translocations
By
Luis Hernández,
Magda Pinyol,
Silvia Hernández,
Silvia Beà,
Karen Pulford,
Andreas Rosenwald,
Laurence Lamant,
Brunangelo Falini,
German Ott,
David Y. Mason,
Georges Delsol, and
Elias Campo
From the Laboratory of Pathology, Hospital Clinic, Institut
d'Investigacions Biomediques August Pi i Sunyer, University of
Barcelona, Barcelona, Spain; LRF Immunodiagnostics Unit, Nuffield
Department of Clinical Biochemistry and Cellular Science, John
Radcliffe Hospital, Oxford, UK; Institute of Pathology, University of
Würzburg, Würzburg, Germany; Laboratory Department of
Pathology and UPCM-ERS 1590 CNRS, CHU Purpan, Toulouse, France;
Institute of Hematology, Perugia University, Perugia, Italy.
 |
ABSTRACT |
Anaplastic large cell lymphoma (ALCL) is associated with the
t(2;5)(p23;q35), which generates the NPM-ALK fusion gene
encoding an 80-kD protein. Several studies have
suggested that genes other than NPM may be fused to the
ALK gene. Here we have identified TRK-fused gene
(TFG) as a new ALK partner in 2 ALCL, 1 of which exhibited a t(2;3)(p23;q21). In these cases, TFG was involved in 2 different fusion genes, TFG-ALKS and
TFG-ALKL, coding respectively 85-kD and
97-kD chimeric proteins. The ALK breakpoint in these
translocations was the same as in the classic t(2;5) translocation.
These 2 proteins were both active in an in vitro tyrosine kinase assay
showing that the new cloned cDNA sequences are translated into chimeric
proteins with functional activity. These findings indicate that
TFG can provide an alternative to NPM as a fusion
partner responsible for activation of the ALK and the
pathogenesis of ALCL.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
ANAPLASTIC LARGE cell lymphoma (ALCL)
is associated with the (2;5)(p23;q35) translocation,1,2
which fuses the nucleophosmin (NPM ) gene on chromosome 5q35
to the anaplastic lymphoma kinase (ALK ) gene on chromosome
2p23.3 This rearrangement leads to the production of a
novel 80-kilodalton (kD) fusion protein with transforming properties in
which the N-terminal region of nucleophosmin is linked to the
C-terminal region of ALK containing the tyrosine kinase catalytic
domain.3-6 Similarly to other genes responsible for
activating receptor tyrosine kinase oncogenes, NPM is
constitutively expressed in all tissues, and activates the catalytic
domain of the ALK segment through dimerization.5,7,8 The
function of normal NPM is to shuttle ribonucleoproteins from the
cytoplasm to the nucleus,7,8 and heterodimerization between normal and chimeric NPM probably explains the immunohistochemical detection of ALK in the nucleus as well as in the cytoplasm of tumor
cells harboring the t(2;5)(p23;q35). However, this nuclear localization
of the protein is not required for malignant
transformation.5,6
Several cytogenetic and molecular studies have now suggested that
translocations other than the classic t(2;5)(p23;q35) may also activate
the ALK gene and participate in the pathogenesis of
ALCL.9-17 Interestingly, ALK protein expression in ALCL
negative for NPM-ALK translocation is restricted to the
cytoplasm of the tumor cells.10,12,13,18 Recently,
biochemical study of ALK protein in NPM-ALK-negative ALK-positive ALCL
has detected novel ALK proteins with kinase activity and different
molecular weights ranging from 85 to 113 kD.19 These
observations indicate that genes other than NPM may also
deregulate ALK and participate in the pathogenesis of ALCL, and
recently, Lamant et al20 have found nonmuscular tropomyosin
(TPM3) gene as the partner fused with ALK gene in a
t(1;2)(q25;p23) translocation present in a case of ALCL.
In this study, we have identified the TFG (TRK-fused
gene) gene as a new fusion partner for ALK in 2 cases of
ALCL. In these cases, 2 structurally different translocations created
TFG-ALK fusion genes encoding chimeric proteins of different molecular weight (85 kD and 97 kD) that showed tyrosine kinase activity in vitro.
| |
MATERIALS AND METHODS |
Materials.
The material used for the initial cloning experiments was a diagnostic
lymph node biopsy from a 19-year-old man (case #789), which showed the
typical features of "common"-type ALCL. However, reverse
transcription-polymerase chain reaction (RT-PCR) analysis provided no
evidence for the NPM-ALK fusion gene, and ALK protein was
expressed with a cytoplasmic restricted pattern.
After identification of the TFG-ALK chimeric gene (see below),
6 additional cases of ALCL that lacked NPM-ALK and
TPM3-ALK were examined by RT-PCR. One of these later cases
(case #862) exhibited the t(2;3)(p23;q21) described
previously.17 Expression of normal TFG transcripts
was also examined by RT-PCR (see below) in 3 non-neoplastic lymphoid
tissues, 14 non-Hodgkin's lymphomas (NHLs), and 11 malignant
hematopoietic cancer cell lines (8402, CEM, U937,
HL-60, Karpas 299, MOLT-4, K562, Raji, Ramos, Namalwa, and HSB2). The
SU-DHL-1 and Karpas 299 cell lines (both of which carry the (2;5)
translocation) were used as positive controls.
Immunohistochemistry and antibodies.
Immunohistological staining was performed using a panel of monoclonal
antibodies for B- and T-cell antigens, together with antibodies to CD30
(Dako-BerH2), and EMA (Dako-EMA/E29). Antibodies against ALK protein
(ALK1 and ALKc) and the N-terminal region of nucleophosmin (NA24) used
in the immunohistochemical and Western blot analysis were produced in
the authors' laboratories.10,13,21
Western blotting and in vitro kinase assay.
Cryostat sections (6 µm) were cut from frozen samples of normal
tonsil and the biopsy specimens from cases no. 789 and 862. Cytocentrifuge preparations were made of the cultured SU-DHL-1 cell
line. Western blotting using the monoclonal anti-ALK (ALKc) or anti-NPM
(NA24) and an in vitro kinase assay were performed as previously
described.19
RNA extraction and 5' RACE reaction.
Total RNA was isolated from a frozen sample of the diagnostic lymph
node using guanidine isothiocyanate extraction and cesium chloride
gradient centrifugation. cDNA was obtained from 1 µg of total RNA
using 2.5 pmol/L of GSP1 ALK-specific primer
(5'-ACCCCAATGCAGCGAACAA-3') and Super Script II Reverse Transcriptase
(Life Technologies Inc, Paisley, UK). The RACE technique was used to
obtain the 5' sequence fused with the ALK gene following the
manufacturer's recommendations. The PCR primers used for 5' RACE
reaction were AAP primer (included in the kit) and GSP2 ALK
primer (5'-CTGGTGGTTGAATTTGCTGAT-3') for the first round and AUAP
primer (included in the kit) together with GSP3 ALK primer
(5'-CTTGGGTCGTTGGGCATTC-3') for the second nested round of PCR
amplification. The specificity of the PCR fragments obtained were
confirmed by hybridization with the fluorescein-labeled internal
oligonucleotide ALK 3 (5'-GTCGAGGTGCGGAGCTTGCTCAGC-3').
DNA sequencing.
The PCR products were purified from the gel and sequenced in ABI PRISM
automated sequencer (Applied Biosystems, Foster City, CA). Both DNA
strands were completely sequenced using different upstream and
downstream primers by primer walking.
RT-PCR expression analysis of NPM-ALK, TPM3-ALK, TFG and
TFG-ALK genes.
cDNA from all the analyzed samples was obtained from 1 µg of total
RNA, random hexamer priming and SuperScriptTM II Reverse Transcriptase
(Life Technologies Inc) following the manufacturer's recommendations.
Amplification of the RPS14 ribosomal mRNA was performed as control.
NPM-ALK and TPM3-ALK expression was examined using
previously described methods.3,19 Expression analysis of
wild-type TFG gene was performed using TFG2
(5'-AACATCCTGGAGTCCACCATG-3') and TFG4D (5'-GCCCTGAAACCTGATCATCTG-3')
primers to amplify a 601 bp fragment from 2 µL of cDNA. The PCR
conditions were 35 cycles consisting of 45 seconds at 94°C, 45 seconds at 65°C and 45 seconds at 72°C, followed by a final
extension of 20 minutes at 72°C. The PCR mixture contained 1 U of Taq
(Boehringer Mannheim, Mannheim, Germany), 0.8 mmol/L each primer, 100 mmol/L dNTPs, and PCR buffer in a final volume of 25 µL.
TFG-ALK expression analysis was assessed using a set of primers
containing the translocation breakpoint described in this study. The
primers used were TFG1 (5'-AGCTTGGAACCACCTGGAGAACC-3')/ALK3.
| |
RESULTS AND DISCUSSION |
The lymph node biopsy specimen of case no. 789 showed a typical ALCL of
"common" morphology with a T-cell phenotype (CD3-positive, CD5-positive) coexpressing CD30 and EMA. ALK protein was detected in
all tumor cells but was restricted to the cytoplasm. RT-PCR studies for
NPM-ALK and TPM-ALK chimeric products were negative. Western blot analysis (using ALKc antibody) detected an ALK protein with an apparent molecular weight of 85 kD, higher than the 80 kD of
the classic NPM-ALK fusion protein.19 Immunohistochemical studies using a monoclonal antibody against the N-terminal portion of
NPM only detected nuclear NPM. This was in contrast to the cytoplasm
and nuclear distribution of NPM observed in cases of t(2;5)-positive
NPM-ALK-positive ALCL.6,10 Furthermore, Western blotting
studies only detected the presence of wild-type 38-kD NPM (Fig
1A). These observations confirmed at the
protein level that NPM was not fused to ALK in this tumor. However, an
in vitro kinase assay showed that the ALK portion of the novel protein present in this tumor possessed tyrosine kinase activity (Fig 1B).
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| Fig 1.
Biochemical assays of proteins extracted from
cytocentrifuge preparations and cryostat tissue sections. (A) Western
blotting. Anti-ALK (ALKc) identifies the 80-kD NPM-ALK protein present
in lysates of SU-DHL-1 cells. This protein is also detected by anti-NPM
(NA24). In contrast, anti-ALK detects a protein of 85 kD in lysates
from case #789 and a protein of 97 kD in lysates from case #862 but
only wild-type 38-kD NPM are present in these cases. Normal tonsil
contains no ALK protein and only wild-type NPM. (B) In vitro kinase
assay. Kinase activity is present in the 80-kD NPM-ALK protein present
in the SU-DHL-1 cell line, in an 85-kD ALK protein present in case
#789, and in a 97-kD ALK protein present in case #862. No corresponding
band is detected in the tonsil used as negative control.
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To identify the gene involved in this new ALK translocation, we
used a 5'RACE strategy. The primers for this technique were designed
within the known 3' catalytic domain of the ALK. The result of
the 5' amplification yielded a major product of approximately 800 bp.
Hybridization with an internal ALK primer confirmed the specificity of this product, which was subsequently purified, cloned,
and sequenced.
The sequence of this fragment confirmed that a gene other than
NPM was fused to the 5' region of ALK. Comparison of
this sequence with the Genbank database showed 99.7% homology with the
5' region of the TFG gene (TRK-fused gene), which has
been mapped to chromosome 3q11-12.22 This gene was
initially identified as the rearranged partner of the NTRK1
gene in a thyroid papillary carcinoma generating the TRK-T3
fusion gene that has transforming activity in different models.23 Interestingly, the TFG gene, in common
with other genes which can cause oncogenic activation of receptor
tyrosine kinase genes, is constitutively expressed in many different
tissues.23 To determine whether the TFG gene is
also expressed in lymphoid cells, we analyzed different lymphoid
samples by RT-PCR and could show that wild-type TFG was
constitutively expressed in all non-neoplastic lymphoid tissues, in 14 NHLs, and in 11 neoplastic hematopoietic cell lines.
Using primers from the 5' TFG and 3' ALK distal regions
we could amplify by RT-PCR a 2.5-Kb fragment containing the full-length TFG-ALK coding sequence. The 5' TFG segment was
composed of 459 bp containing 44 bp of the 5' untranslated region and
415 bp of the coding sequence. This region included the predicted
coiled-coil oligomerization domain of the protein (Fig
2A). The breakpoint was located at 415 bp
from the initial methionine. The only difference between the
TFG coding sequence obtained in our case and that previously
described (GenBank accession number Y07968) was a single nucleotide
change in codon 13 (GTC  ATC; Val Ile). This change seems to
be a polymorphic variant because it was also present in genomic DNA
obtained from normal epithelial cells of the patient.
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| Fig 2.
Nucleotide and deduced amino acid sequences of
TFG-ALK cDNA in short TFG-ALKS (A) and long
TFG-ALKL (B) forms. (A) Nucleotide sequence was numbered
according to the previously described sequences. The putative
coiled-coil domain of the TFG sequence is underlined. The
asterisk marks a previously undescribed polymorphism (gtc atc;
Val Ile). The translocation breakpoint in the cDNA is marked with
an arrow. (B) The additional 165 bp TFG sequence is underlined.
The translocation breakpoint in the cDNA is marked with an arrow.
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The ALK sequence in our case was identical to that previously
described,3 and it was in frame with the upstream
TFG open reading frame. Noticeably, the ALK breakpoint
in this TFG-ALK cDNA was the same as that found in the
NPM-ALK fusion gene. The predicted chimeric TFG-ALK protein was
composed of 701 aminoacids, 138 of which were encoded by the
TFG gene and 562 by the ALK gene. The valine in
position 139 is encoded by a new codon created by the rearrangement.
The predicted molecular weight of the new TFG-ALK fused protein is 83 kD, which is very similar to the value obtained by Western blot
analysis (85 kD).19
To determine if this new TFG-ALK translocation was expressed in
other ALCLs, we analyzed 6 additional tumors with ALK protein expression restricted to the cytoplasm and which were negative for
NPM-ALK and TPM3-ALK translocations. In addition, 3 NPM-ALK-positive and 1 TPM3-ALK-positive ALCL, and 5 thyroid carcinomas were also analyzed. Expression of the
TFG-ALK chimeric product was examined with a set of primers
from TFG and ALK genes spanning 141 bp of the
breakpoint region. The TFG-ALK chimeric transcript could be amplified only in our control tumor and also in 1 ALCL (case #862) that
was negative for NPM and TPM3-ALK translocations. The
cytogenetic analysis of this tumor had shown the presence of a
(2;3)(p23;q21) translocation.17 Interestingly, however, the
amplified product in this case showed an unexpected larger size (306 bp) than that obtained (141 bp) in our control case. Sequencing of this
product confirmed a TFG-ALK rearrangement in which the
ALK breakpoint was the same as in the other ALK
translocations. However, the TFG fragment contained an
additional 165 bp sequence from the TFG gene not present in the
hybrid gene in our previous case (Fig 2B). However, the TFG
breakpoint region in this second case was the same as in the
TFG-NTRK1 translocation in thyroid carcinomas.23 In
this new rearrangement creating a larger TFG-ALK
(TFG-ALKL) gene, the additional 165 bp
TFG sequence was also in frame with the 5' TFG fragment
of our previous shorter TFG-ALK
(TFG-ALKS) translocation, and with the
distal 3' ALK sequence. The predicted molecular weight of this
new chimeric TFG-ALKL protein was 96 kD, in
keeping with the value of 97 kD determined by Western blot and in vitro
kinase analysis of this case (Fig 1).
These findings indicate that TFG is an alternative to
NPM as a partner for ALK in ALCL, and that it can be
involved in 2 structurally different translocations,
TFG-ALKL, encoding 85-kD and 97-kD chimeric
proteins, respectively. An in vitro kinase assay showed that these
proteins also had tyrosine kinase activity (Fig 1) indicating that the
new cloned cDNA sequences are translated into chimeric proteins with
functional activity. The 5' TFG segment included in this
translocation contains the full predicted coiled-coil oligomerization
domain of the gene. Similarly to the 5' region of NPM in the
NPM-ALK translocation, this TFG domain is absolutely required for oligomerization and transforming activity of
TFG-NTRK (TRK-T3) oncogene.24 Therefore, it
is also possible that TFG may play a similar role in the
activation of ALK in ALCL. However, in distinction to
NPM, the TFG gene lacks nuclear-signaling domains, which is in keeping with the restricted cytoplasmic pattern of ALK expression observed in our tumors. These findings support previous in vitro experiments, indicating that the oncogenic activity of rearranged ALK is independent of the nuclear
localization.5,6
| |
FOOTNOTES |
Submitted March 10, 1999; accepted July 1, 1999.
L.H. and M.P. contributed equally to this study.
Supported by The Leukemia Research Found (Grant No. #94/46); the
Comision Interministerial de Ciencia y Tecnologia (SAF 99/20), Asociacion Española Contra el Cancer, CIRIT, Generalitat de
Catulunya (98SGR21); and the AIRP (Associasione Italiana per la Ricerca sul Cancro). Genbank accession numbers for the TFG-ALKS and
TFG-ALKL sequences are AF125093 and AF143407, 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 Elias Campo, MD, Laboratory
of Pathology, Hospital Clinic, Villarroel 170, 08036-Barcelona, Spain;
e-mail: campo{at}medicina.ub.es.
| |
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Fusion of H4/D10S170 to the Platelet-derived Growth Factor Receptor {beta} in BCR-ABL-negative Myeloproliferative Disorders with a t(5;10)(q33;q21)
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Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like)
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TOP
ABSTRACT
INTRODUCTION