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NEOPLASIA
From the First Department of Internal Medicine, Nagoya
University School of Medicine, Nagoya, Japan.
The TEL gene on 12p12-13 is a target for a number of
translocations associated with various hematological malignancies.
The fusion of the TEL gene to the Syk
gene in a patient with myelodysplastic syndrome (MDS) with
t(9;12)(q22;p12) is reported. Southern blot analysis of patient bone
marrow cells with TEL and Syk gene probes detected rearranged fragments. Anchored polymerase chain reaction identified the Syk gene, a nonreceptor tyrosine kinase, on
9q22 fused downstream of TEL exon 5. The TEL
gene was fused in-frame to Syk and produced a fusion
protein that was constitutively phosphorylated in tyrosine with
dimerization that was mediated by the helix-loop-helix domain
of TEL. A TEL-Syk fusion product transformed
the murine hematopoietic cell line BaF3 to interleukin-3 growth factor
independence. TEL-Syk is a novel transforming protein and leads to the
transformation of hematopoietic cells. These data implicate that the
rearranged Syk gene is involved in the pathogenesis of
hematopoietic malignancies.
(Blood. 2001;97:1050-1055) The chromosomal translocations frequently observed in
human malignant cells are known to represent a crucial step to
carcinogenesis.1 Recent molecular studies have shown that
the TEL gene located on 12p12-13 (also known as the E26
transforming-specific [ETS] translocation variant gene 6, ETV6) is frequently involved in chromosomal translocations
in a variety of human leukemias.2 The TEL gene
codes for a ubiquitously expressed nuclear protein that possesses a
predicted pointed domain (PNT domain, also referred to as
helix-loop-helix oligomerization domain) at its N-terminal end and an
ETS DNA-binding domain at its C-terminal. TEL has been found
fused to several partner genes including receptor tyrosine kinases,
PDGFR The TEL gene was initially identified by cloning the
t(5;12)(q33;p13) associated with chronic myelomonocytic leukemia
(CMML).2 The TEL-PDGFR The Syk gene located on 9q22 encodes a nonreceptor
protein tyrosine kinase consisting of 2 tandem Src-homology 2 (SH2)
domains and a catalytic domain at C-terminal end.19,20
Syk is widely expressed in hematopoietic cells. Its
activation has been implicated in a variety of hematopoietic cell
responses including the Fc gamma receptor, B-cell antigen receptor,
immunoglobulin E (IgE) receptor, several interleukin (IL) receptors,
integrin, and We have previously reported a case of MDS with t(9;12)(q22;p12) that
involved the TEL gene using the fluorescence in situ hybridization technique.27 This case presented with
eosinophilia (9%), dry cough, and skin involvement progressing to
leukemic transformation with megakaryocytic blast. We now report that
the consequence of t(9;12)(q22;p12) is a TEL-Syk fusion gene
which results in a novel activation of Syk due to its fusion
to the TEL gene.
Southern blot analysis
RNA preparation and Northern blot analysis
Anchored PCR and RT-PCR Anchored PCR was adapted from the method of Frohman with minor modifications. A total of 5 µg RNA was treated with DNase (deoxyribonuclease) (Amersham Pharmacia) and reverse transcribed using Moloney murine leukemia virus (MMLV)-RT (Gibco-BRL, Grand Island, NY) and primer QT, 5'-TGAGCAGAGTGACGAGGACTCGAGCTCAAGCTTTTTTTTTTTTTTTT-3'. An aliquot of cDNA was used as a template for 35 cycles of PCR at 94°C for 40 seconds, 58°C for 1 minute, and 72°C for 6 minutes with TEL41F, 5'-CTCAGTGTAGCATTAAGCAGGAACG-3', and primer Q0, 5'-CCAGTGAGCAGAGTGACG-3'. A second round of amplification was then performed using nested TEL338F, 5'-GATCTCCTCATTCAGGTGCTGTG-3', and primer Q1, 5'-GATCTCCTCATTCAGGTGCTGTG-3'.30 The resulting 1500-bp product was cloned into the plasmid vector, pBluescript SK( )
(Stratagene, La Jolla, CA), and sequenced. The DNA sequence was sent to
the BLAST (Basic Logical Alignment Search Tool) server at the National
Institutes of Health (NIH), Bethesda, MD, to compare with GenBank.
For RT-PCR, total RNA was converted to single-stranded cDNA using oligo(dT) primers and MMLV-RT. We performed PCR amplification with Taq DNA polymerase (Perkin-Elmer Biosystems Japan, Tokyo, Japan) for 30 cycles using oligonucleotide primers at 94°C for 40 seconds, 65°C for 1 minute, and 72°C for 1 minute. The 5' and 3' TEL primers were TEL925F and 1202R, and the 5' and 3' Syk primers were Syk738F and Syk1112R, respectively. PCR reaction products were then electrophoresed on 1.5% agarose gels and stained with ethidium bromide. DNA constructs and expression plasmids Full-length Syk, TEL-Syk, and Syk-TEL cDNAs were constructed by PCR. The primers used to generate TEL PNT mutant by PCR
amplification were: TEL206R, 5'-GGCGACGTCATCCCTGCTCC-3'; and TEL442F,
5'-AGCCGGACGTCATACTGCAT-3', resulting in the deletion of nt 222-461 of
the TEL gene. PCR products were confirmed by sequencing to
be devoid of mutations. We used CMV early promoter-based expression
vector pcDNA3.1 (Invitrogen, San Diego, CA) and influenza hemagglutinin
(HA) epitope-tagged vector pHM6 (Roche Molecular Biochemicals,
Indianapolis, IN). Flag epitope-tagged vector pFlag and retroviral
expression vector pBabeNeo have been described,
respectively.31,32 TEL-Syk, TEL PNT-Syk, and
Syk constructs were cloned into pcDNA3.1 and pFlag (pF-TS, pF-T PS,
and pF-S); TEL-Syk was cloned into pHM6 (pH-TS); and TEL-Syk, Syk-TEL,
and TEL PNT-Syk were cloned into pBabeNeo (pB-TS, pB-ST, and pB-T
PS), respectively.
Antibodies The antibodies used were anti-Syk monoclonal antibody (mAb) (Upstate Biotechnology Inc, Lake Placid, NY), antiphosphotyrosine mAb horseradish peroxidase (HRP)-conjugated PY-20 (ICN Biochemicals, Aurora, OH), anti-Flag mAb (Eastman-Kodak Company, New Haven, CT), and HRP-conjugated anti-HA mAb (Roche). Anti-Syk mAb was directed against nt 1083-1163 of Syk.Cell transfection assays COS-7 cells were maintained in Dulbecco modified Eagle medium (DMEM) supplemented with 10% fetal calf serum (FCS). pF-TS, pF-TPS,
and pF-S were cotransfected with pH-TS into subconfluent COS-7 cells by
the calcium-phosphate technique (20 µg per transfection).
The pCMV-G containing vesicular stomatitis virus envelope glycoprotein
was cotransfected with pB-TS, pB-ST, and pB-T Immunoprecipitation and Western blot analysis Cells were solubilized in lysis buffer comprising 20 mM Tris-HCL (tris[hydroxymethyl] aminomethane-hydrochloride) (pH 7.4), 0.1% sodium dodecyl sulfate (SDS), 1% Triton X-100, and 1% sodium deoxycholate. The cell lysates were precleared by incubation with protein G-agarose (Gibco) overnight and centrifuged. The supernatants were incubated with the indicated antibodies for 1 hour followed by 20 µL 50% (vol/vol) protein G-agarose for 2 hours at 4°C. The immunoprecipitates were washed 3 times in lysis buffer. For immunoblotting, the precipitates were boiled with electrophoresis SDS sample buffer for 3 minutes. Whole cell lysates or immunoprecipitates were separated by SDS-PAGE (polyacrylamide gel electrophoresis) and transferred onto polyvinylidine difluoride (PVDF) membranes (Bio-Rad Laboratories, Hercules, CA). The membrane blots were blocked with 5% skim milk in Tris-buffered saline (TBS) containing 0.1% Tween 20 (TBS-T) or with blocking buffer comprising 15 M sodium chloride (NaCl), 10 mM/M malic acid, and 1% blocking reagent (pH 7.5) for the detection of PY-20 (Roche) for 1 hour at 37°C followed by incubation with primary antibodies in TBS-T for 2 hours at room temperature. Following washing, membranes were incubated with HRP-linked whole antimouse IgG antibody (Amersham Pharmacia) in TBS-T for 2 hours at room temperature. After washing, the enhanced chemiluminescence (ECL) assay was performed, and positive bands were identified on x-ray films.
Identification of TEL-Syk in MDS Southern blots of DNA from the patient's BM mononuclear cells with t(9;12), hybridized with the TEL probes T1 (data not shown) and T2 and the Syk probe S, are shown in Figure 1. With probe T2, rearranged fragments were detected in each restriction digest of the patient's DNA, suggesting that the chromosome 12 breakpoint is localized to TEL exon 5-7. To identify the fusion partner on chromosome 12, we used anchored PCR with TEL primers to amplify the fusion transcript from the patient's BM cell cDNA. The resulting 1500-bp PCR product was cloned and sequenced. A database search showed that TEL was fused to nt 993 of exon 5, the sequence being completely identical to the Syk gene (Figure 2). We also confirmed the presence of rearranged bands detected with Syk probe S by Southern blot analysis.
Expression of TEL-Syk fusion gene Expression of the TEL, Syk, and TEL-Syk genes was examined by Northern blot analysis of RNA isolated from a blood sample of the same patient and HL-60 cell line (Figure 3). Wild-type 5.6- and 2.8-kb Syk transcripts and 6.5-, 4.5-, and 2.4-kb TEL transcripts were detected in HL-60 with the Syk probe S and the TEL probe T2, whereas novel 4.2- and 1.8-kb transcripts were specifically detected in the patient.
Identification of TEL-Syk and Syk-TEL fusion transcript RT-PCR analysis was performed to confirm the fusion transcripts between the TEL and Syk genes. We detected expression of TEL, Syk, TEL-Syk, and Syk-TEL genes in patient's BM cells upon initial diagnosis (Figure 4). The TEL-Syk and Syk-TEL fusion products were also detected at remission phase but not at postallogeneic BM transplantation (day 220).
Mitogenic properties of the TEL-Syk To analyze the importance of TEL-Syk for its mitogenic properties, we made use of the ability of the IL-3-dependent BaF3 to become independent of IL-3 for survival and proliferation. The IL-3-dependent murine leukemia BaF3 cells were infected with pB-TS, pB-ST, and pB-T PS by retrovirus methods (Figure
5). Cells were allowed to recover for 48 hours in growth medium plus IL-3 and then selected for G418 resistance
for 2 weeks. To assay for IL-3 independence, infectants were switched
to growth medium without IL-3. In the absence of IL-3, only the BaF3
cells with the intact TEL-Syk were found to be able to
proliferate under these conditions (Figure
6).
TEL-Syk is constitutively tyrosine-phosphorylated in vivo Previous experiments have shown that TEL-induced oligomerization mediated by the PNT domain of TEL results in activation of TEL-PDGFR tyrosine kinase
activity.4,7,17,18 To investigate whether
TEL-Syk is constitutively tyrosine-phosphorylated, we compared the autophosphorylation of TEL-Syk and TEL PNT-Syk in which
the oligomerization domain (amino acids 66-145) was deleted. TEL-Syk
and TEL PNT-Syk proteins expressed in COS-7 cells (pF-TS and pF-T
PS were transfected) were immunoprecipitated by the anti-Syk mAb.
Subsequently, the immunoprecipitates were separated by SDS-PAGE and
transferred to PVDF membrane. Blots were probed using an
antiphosphotyrosine mAb (Figure 7). A
prominent 100-kd tyrosine-phosphorylated protein was only detected in
TEL-Syk. Subsequent stripping and reprobing with the anti-Flag mAb
confirmed that TEL-Syk and TEL PNT-Syk were equally
immunoprecipitated.
To investigate TEL-induced oligomerization properties,
we compared the properties of intact TEL-Syk with TEL
Here we showed the existence of new fusion genes
TEL-Syk and Syk-TEL as a result of the
t(9;12)(q22;p12) with MDS. In TEL-Syk transcript, exons 1-5 of TEL containing the PNT domain, are fused to
Syk containing a part of the C-terminal SH2 and the complete protein kinase domain. We also showed that the TEL-Syk
fusion gene results in the constitutive activation of Syk
kinase activity and demonstrates mitogenic potency. The reciprocal
fusion protein, Syk-TEL, containing the SH2 domains and an ETS
DNA-binding domain did not acquire transforming potency. It is
well-established that receptor tyrosine kinases are activated by
dimerization.35,36 However, most nonreceptor kinases are
activated through transphosphorylation events involving receptor or
other nonreceptor kinases. Recent experiments have shown that the
TEL gene contributes to the pathogenesis through
constitutive activation of the protein kinase which results in fusion
of TEL to another nonreceptor tyrosine kinase, the
ABL7 and JAK2 genes4;
this fusion is similar to the TEL-PDGFR Here we reported that the TEL-Syk fusion induces
oligomerization and results in constitutive activation of
Syk as assessed by tyrosine autophosphorylation. The
TEL-Syk fusion is an oncoprotein that transforms the hematopoietic
cell line BaF3 to growth factor independence. On the other hand, TEL This is the first report to demonstrate the involvement of Syk in the pathogenesis of leukemia. Syk is a nonreceptor tyrosine kinase, and the localization of Syk to the receptor is mediated through a high-affinity interaction between the SH2 domain of Syk and immunoreceptor tyrosine-based activation motif (ITAM) that is present in several receptors.37 The phosphorylation event of Syk is required for subsequent downstream signaling: activation of the Ras-MAPK and Rac1-JNK pathways as well as cytokine expression.22,23,38 However, little is known about the activation mechanism of Syk without receptors. A recent study showed that cytoplasmic protein tyrosine kinase is maintained in an auto-inhibited state by means of intramolecular interactions between the SH2 and catalytic domain, and this conformational change contributes to the activation.39 We favor the hypothesis that Syk dimerization may be necessary for tyrosine kinase activation and subsequent activation of Syk-dependent signaling pathways. The TEL-Syk fusion gene may provide a novel tool for the analysis of the Syk-mediated signal transduction. The patient with MDS in this study received allogeneic BM transplantation at first remission due to the presence of malignant cells with t(9;12) detectable by RT-PCR at complete remission. The transcripts were identified at remission phase but not at postallogeneic transplantation. Detection of fusion transcripts by RT-PCR was important for the evaluation of a clinical cure and the presence of minimal residual disease at the level of stem cells. In conclusion, this is the first demonstration that Syk plays an important role in malignant progression. The data presented here support the hypothesis that ectopic constitutive activation of Syk resulting from the TEL-Syk fusion increases activation of several signal pathways and demonstrates the oncogenic potential of Syk. In future experiments, we will attempt to clarify whether the constitutive activation of Syk is expressed in various hematological malignancies and whether a specific signal transduction pathway after activation by TEL-Syk is alternated in normal Syk signaling pathway.
We thank Drs Kaoru Tohyama, Fumihiko Hayakawa, Akihiro Tomita, and Kazuhito Yamamoto for helpful discussions and Satoru Suzuki and Chika Wakamatsu for their excellent technical assistance.
Submitted May 4, 2000; accepted October 16, 2000.
Supported in part by Grants-in-Aid for Scientific Research (no. 10670941) from the Ministry of Education, Science and Culture of Japan, Japan.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Yoshie Kuno, First Department of Internal Medicine, 65 Tsurumaicho, Showaku, Nagoya 466-8550, Japan; e-mail : kunoy{at}tsuru.med.nagoya-u.ac.jp
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Abstract
Introduction
II
