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[Cancer Research 61, 8371-8374, December 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Fusion of ETV6 to Fibroblast Growth Factor Receptor 3 in Peripheral T-Cell Lymphoma with a t(4;12)(p16;p13) Chromosomal Translocation1

Fumiharu Yagasaki2, Daisuke Wakao, Yasuko Yokoyama, Yumiko Uchida, Ikuo Murohashi, Hidekazu Kayano, Masafumi Taniwaki, Akira Matsuda and Masami Bessho

First Department of Internal Medicine [F. Y., D. W., Y. U., A. M., M. B.], Chromosome Unit, Central Laboratories [Y. Y.], and Department of Pathology [H. K.], Saitama Medical School, Saitama 350-0495; Department of Medical Technology, Saitama Prefectural University, Saitama [I. M.]; and Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto [M. T.], Japan


   ABSTRACT
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 ABSTRACT
Introduction
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 Results and Discussion
 REFERENCES
 
Fusions of the ETV6/TEL gene to receptor or protein tyrosine kinases (TKs), such as PDGFRß, JAK2, ABL, ABL2, TRKC, and Syk, have been reported in various hematological malignancies. Expression of the resultant chimeric proteins is believed to lead to constitutive TK activity through activation by the helix-loop-helix (HLH) domain of ETV6. We identified a novel ETV6 partner gene, fibroblast growth factor receptor 3 (FGFR3), in a patient with peripheral T-cell lymphoma (PTCL) with a t(4;12)(p16;p13) translocation. The ETV6-FGFR3 transcript showed a fusion of exon 5 of ETV6 to exon 10 of FGFR3, resulting in an open reading frame for a chimeric protein consisting of the HLH domain of ETV6 and the TK domains of FGFR3. This is the first report of ETV6 and FGFR3 involvement in PTCL.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Although there are many reports concerning chromosomal abnormalities in hematological malignancies, cytogenetic studies of PTCL3 have been based on limited numbers of patients and rarely showed consistent chromosomal abnormalities. We identified a novel chromosomal translocation, t(4;12)(p16;p13), in a patient with PTCL. Both chromosomal breakpoints are of special interest because rearrangement of the ETV6 gene (also known as TEL) is associated with various hematopoietic malignancies, with translocation of 12p13, and the fibroblast growth factor receptor 3 (FGFR3) on 4p16 frequently is involved in multiple myeloma, with t(4;14)(p16;q32) (1) .

ETV6, initially cloned as a partner gene of platelet-derived growth factor receptor (PDGFRß) in a t(5;12)(q33;p13) translocation, is a member of the ETS family of transcription regulators (2) . Since its discovery, ETV6 has been reported to fuse to a number of different partner genes such as MDS1/EVI1(3q26) (3) , BTL(4q11) (4) , ACS2(5q31) (5) , STL(6q23) (6) , JAK2(9p24) (7, 8) , ABL(9q34) (9, 10) , CDX2(13q12) (11) , TRKC(15q24) (12) , AML1(21q22) (13 , 14) , MN1(22q11) (15) , ARG(1q25) (16 , 17) , ARNT(1q21) (18) , and Syk (9q22) (19) and to contribute to tumorigenesis in various ways. The most precisely defined mechanism of transformation by ETV6-TEL fusion products is through constitutive kinase activation by the HLH domain of ETV6 in ETV6-protein or ETV6-receptor TK chimeras. We report here the identification of FGFR3 as an additional receptor TK partner of ETV6 in a t(4;12)(p16;p13) translocation found in a case of PTCL.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Patient.
The patient was a 63-year-old woman who was admitted to our hospital with a high fever and enlargement of the cervical, axillary, and inguinal lymph nodes. Her lymph node biopsy specimen was positive for CD3 and CD4, but negative for CD20, CD79a, CD56, and S-100, using immunohistochemistry. A BM aspiration revealed that 2.8% of the BM nuclear cells were lymphoma cells with the same phenotype. Cytogenetic analysis of her BM cells showed 46,XX,t(4;12)(p16;p13) [3]/49,XX,+i [1](q10),t(4;12)(p16;p13),+10,+19 [10]/49,XX,+i [1](q10),t(4;12)(p16;p13),+11,+19 [3]/46,XX [4]. Her serum was negative for HTLV-1 antibody. After diagnosis of PTCL, she underwent chemotherapy according to the modified CHOP protocol. After initial chemotherapy, her lymph node swelling showed generally improvement but cytogenetic analysis of her BM cells showed 46,XX, t(4;12)(p16;p13) [2], 46,XX [18].

FISH.
Metaphase FISH analysis was performed on the BM samples as described previously (5) . The slides were examined under an E-800 fluorescence microscope (Nikon, Tokyo, Japan) and the FISH images were captured using a CCD camera (Cohu, San Diego, CA). Separate images of 4',6-diamidino-2-phenylindole (DAPI)-stained chromosomes and fluorescein signals were enhanced and merged using Q-FISH software (Leica, Tokyo, Japan). Ten to 20 abnormal metaphase cells were analyzed in each experiment.

The following probes were used: cosmids 179A6, 50F4, 2G8, 184C4, and 148B6, containing exon 1, exon 2, exon 3, exons 4 and 5, and exon 8, respectively, of ETV6, kindly provided by Professor P. Marynen, Leuven, Belgium (20) and cosmid pC385.12, containing the entire FGFR3 gene, kindly provided by M. R. Altherr (Los Alamos National Laboratory, Los Alamos, NM; Ref. 21 ). The cosmid probes were labeled with biotin-11-deoxyuridine triphosphate and/or digoxigenin-dUTP using a nick translation kit (Boehringer Mannheim, Mannheim, Germany).

RT-PCR for Detection of ETV6-FGFR3 and FGFR3-ETV6 Transcripts.
RT-PCR was performed on the patient’s BM RNA using standard procedures with the following primers: E93F1 (5'-GGAAAAACCTGAGAACTT-3'), specific for the 5'-UTR of ETV6, in combination with FGF-RI (5'-GACCAGTGGCCCTTCACG-3'), specific for the 3'-UTR of FGFR3. To detect reciprocal transcripts, FGF-F2 (5'-ACGAAGACGGGGAGGACGAG-3') was used in combination with TEL-AS1 (5'-GCTGAGGTGGACTGTTGGTT-3'). First-strand cDNA was reverse transcribed from 1 µg of total RNA according to standard procedures, using the oligo(dT) primer. The PCR conditions for each primer pair were as follows: 94°C for 1 min, followed by 40 cycles of 94°C for 20 s, 58°C for 20 s, 72°C for 90 s, and a final extension at 72°C for 10 min.

DNA Sequencing and Analysis.
The RT-PCR products were directly sequenced on an ABI 310 DNA sequencer (Applied Biosystems, Urayasu, Japan). The DNA sequence was sent via Netscape to the BLAST server at NIH4 for comparison with those in GenBank (blastn).

Immunohistology Studies.
Paraffin-embedded samples of normal lymph nodes were obtained from the Departments of Pathology of the Saitama Medical School Hospital (Saitama, Japan) and were used as negative control. Paraffin-embedded lymph node biopsy material from the patient and the control specimen were subjected to immunoperoxidase studies using a rabbit antiserum specific for the COOH terminus of FGFR3 (sc-123; Santa Cruz Biotechnology, Santa Cruz, CA) followed by biotinylated secondary antibodies in conjunction with the Vectastain horseradish peroxidase-conjugated avidin-biotin system with diaminobenzidine tetrahydrochloride (DAB) as the chromogenic substrate (Vector Laboratories, Burlingame, CA).


   Results and Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Two-color FISH analysis with cosmid 184C4, containing exons 4 and 5 of ETV6, and cosmid pC385.12, containing the entire FGFR3 gene, revealed fusion signals on both the der(12) and the der(4), indicating that the breakpoints were within ETV6 and FGFR3 (Fig. 1A)Citation . We were able to perform FISH analysis only on metaphase BM samples from the patient, but careful observation of background interphase nuclei revealed that more than 90% of these were negative for ETV6-FGFR3 fusion signals. Therefore, abnormal metaphases with t(4;12) were thought to be attributable to PTCL cells infiltrating the BM.



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  		Fig. 1. A, two-color FISH analysis of the t(4;12)(p16;p13) translocation. FISH with pC385.12 containing the entire FGFR3 (detected with FITC) and 184C4 (detected with rhodamine). Yellow fusion signals were detected on both der(4) and der(12). Split signals were also detected on der(4) and der(12). These data suggest that the 12p13 breakpoint had occurred in ETV6 and the 4p16 breakpoint had occurred in FGFR3. Additional FISH analyses with ETV6 exon-specific cosmids confirmed that the 12p13 breakpoint was between exon 3 (2G8) and exon 8 of ETV6 (148B6; data not shown). B, expression of FGFR3 protein in PTCL cells. Immunohistochemical staining shows inappropriate strong FGFR3 expression (brown cytoplasmic staining) in numerous lymphoma cells except for residual follicular lymphocytes and endothelial cells (x400). C, the lack of FGFR3 staining of normal lymphoid tissue is shown as negative control (x400).

 
The RT-PCR amplified two products of different sizes (1767 bp and 1618 bp: Fig. 2ACitation , left). Sequence analysis of these amplified products showed they were ETV6-FGFR3 splicing variants (Fig. 2B)Citation . Both transcripts contained an in-frame fusion of ETV6-exon 5 at nt 543 to FGFR3-exon 10 at nt 1270. Unexpectedly, the breakpoints in ETV6 and FGFR3 were both within exons. RT-PCR using various primer sets was performed to avoid a PCR error that long-template cDNA sometimes cannot be amplified by standard PCR technique; however, any premature ETV6-FGFR3 fusion transcripts could not be detected. Although we could not find any hidden splice sites in these exons, according to the GT-AG rule, we conclude that cryptic splicing still seems like a real possibility here, because PCR analysis for genomic breakpoint of the der(4)t(4;12) failed to reveal the direct fusion of these exons (data not shown).



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  		Fig. 2. A, gel analysis of RT-PCR amplified ETV6-FGFR3 fusion transcripts (left) and amplified FGFR3-ETV6 fusion transcripts (right). To the left of the gels, marker sizes (bp). Two specific bands of 1767 bp and 1618 bp (arrowheads, Lane 1) were detected by RT-PCR using primers E93F1 and FGF-RI. The two ETV6-FGFR3 products are the result of an alternative splicing event in the FGFR3 gene, as shown in B. FGFR3-ETV6 fusion transcript (predicted PCR product size, 983 bp) was not detected from this patient’s BM RNA (Lane 3), although a band of ß actin was detected as a positive control (Lane 2). B, part of the nucleotide and deduced amino acid sequence and a schematic diagram of ETV6 and FGFR3 cDNAs and the chimeric fusion transcripts. The positions of the primers used and the size of the resulting PCR products are shown. Nucleotide numbers are derived from the sequences of TEL cDNA and FGFR3 cDNA (GenBank accession nos. HSU11732 and 182568, respectively). An out-of-frame fusion occurred in the 1618-bp splicing variant; *, the resulting stop codon; the alternatively spliced FGFR3 exon 11 is indicated also. Vertical lines, the exon boundaries. DBD, ETS-family DNA-binding domain; TK, protein-TK domain; V, position of trinucleotide insertion.

 
The major, larger product was derived from an in-frame fusion transcript of ETV6-FGFR3, which was predicted to yield a Mr 64,000 chimeric protein comprising the HLH domain of ETV6 and the entire TK domain of FGFR3. Unexpectedly, a trinucleotide insertion (CAG, nt 1303–1306) is present at the very end of FGFR3 exon 11 in this larger transcript. A trinucleotide insertion has not been reported previously in FGFR3. Sequence analysis of full-length ETV6-FGFR3 1767-bp transcripts showed no active mutation previously reported in multiple myelomas (Ref. 22 ; data not shown). In the minor, smaller product, exon 11 of FGFR3 had been spliced out, resulting in a frameshift and generation of a stop codon relatively near to the fusion breakpoint. Conserved-domain database analysis [at National Center for Biotechnology Information (NCBI)] suggests that the short amino acid sequence after the HLH domain has no homology to any functional domain. Further RT-PCR analysis could not detect the reciprocal FGFR3-ETV6 transcript (Fig. 2ACitation , right).

We detected the strong FGFR3 protein expression in lymph node tissue from this patient (Fig. 1B)Citation , using immunohistochemistry with an antiserum specific for the COOH terminus of FGFR3. The lack of staining of normal lymphoid tissue (Fig. 1C)Citation confirmed the previous report that normal hematopoietic cells express FGFR3 at a very low level (1) . These findings imply inappropriate expression of the ETV6-FGFR3 fusion protein.

Recently, Chesi et al. (22) reported the oncogenic potential of overexpression of wild-type and some variant forms FGFR3 with point mutations (22) . However, our data show that the chimeric ETV6-FGFR3 transcript lacks the nucleotide sequence coding for the ligand-binding domain of FGFR3. ETV6-PDGFRß and ETV6-TRKC fusion transcripts result in ligand-independent TK activation through oligomerization of chimeric proteins with the HLH domain from ETV6 (23 , 24) . A similar activation of protein TK (JAK2, ABL, ARG, and Syk), by chromosomal translocation involving ETV6, has been reported to lead to transformation of hematopoietic cells (7 , 10 , 20 , 25) . Therefore, we favor the hypothesis that homodimerization through the HLH domain can lead to a ligand-independent activation of the ETV6-FGFR3 chimeric receptor kinase.

In conclusion, this is the first report of a novel activation mechanism of FGFR3 in cancer as well as in PTCL, in which ETV6/FGFR3 chimeric protein rather than overexpression or activating point mutation of FGFR3 is implicated in tumorigenesis. In the future, additional experiments are needed to elucidate the transforming capability and the function of ETV6-FGFR3 chimeric protein.


   Acknowledgments
 
We thank Dr. Peter Marynen for providing the LL12NCO1 cosmid probes, M. R. Altherr for providing the cosmid pC385.12 containing the entire FGFR3 gene. We also thank Hiromi Miyazaki for cytogenetic analysis and Dr. Akiko Yamamoto for helpful discussions.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by a Grant-in-Aid for Scientific Research of Hematology (13770586) from the Ministry of Education, Culture, Science, Sports and Technology of Japan. Back

2 To whom requests for reprints should addressed, at First Department of Internal Medicine, Saitama Medical School, 38, Morohongou, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. Phone/Fax: 81-492-76-1187; E-mail: fyagasak{at}saitama-med.ac.jp Back

3 The abbreviations used are: PTCL, peripheral T-cell lymphoma; FISH, fluorescence in situ hybridization; ETV6, ets variant gene 6; FGF, fibroblast growth factor; FGFR, FGF receptor; HLH, helix-loop-helix; TK, tyrosine kinase; RT-PCR, reverse transcription-PCR; BM, bone marrow. Back

4 Internet address: http://www.ncbi.nlm.nih.gov. Back

Received 4/18/01. Accepted 10/16/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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