1. Art and Diseño

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TEL Gene Is Involved in Myelodysplastic Syndromes With Either the
Typical t(5;12)(q33;pl3) Translocation or its Variant t(10;12)(q24;p13)
By I. Wlodarska, C. Mecucci, P. Marynen, C. Guo, D. Franckx, R. La Starza, A. Aventin, A. Bosly, M.F. Martelli,
J.J. Cassiman, and H. Van den Berghe
A t(5;12)(q33;p13) translocation is a recurrent chromosome
abnormality in a subgroup of myeloid malignancies with
features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). Themolecular consequence of a
t(5;12) is a fusion betweenthe platelet-derived growth factor
receptor-B gene on chromosome 5 and a novel ETS-like
gene, TEL. on chromosome 12. We report onthree patients
with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations
was investigated by fluorescence in situ hybridization (FISH)
with cosmid probes containing selectively the 5’ end or 3‘
end of TEL. Hybridization of these cosmids t o a der(5)/
der(l0) or a der(l2). respectively, demonstrated a rearrangement of TEL in both translocations, showing that the
t(10;12) is a variant translocation of the t(5;12). Cloning of
the fusion cDNA of one case of t(5;12) showed that the
breakpoint occurred at the RNA level at exactly the same
position as reported by Golub et al (Cell 77:307,1994). In
addition, the TEL gene on chromosome 12 could be localized
between two probes previously mapped to 12~13,namely
PRBl and D12S178, leading t o a better definition of the
position of TEL in this chromosome region. Moreover, in the case
involving chromosome 10, the breakpoint occurred between
cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restrictionmapping
of chromosomal breakpoints strongly suggest that (1)common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no.
5 may be involved and at least a t(10;12)(q24;p13) variant
chromosome translocation does exist in these MDSs, and
(3) both standard and variant 12p/TEL translocations may
be identified byFISH with appropriate probes.
0 1995 by The American Society of Hematology.
C
We report herethree
patients with a typical t(5;12)
(q33;p13) diagnosed as CMML according to the FrenchAmerican-British criteria and one case of refractory anemia
(RA) with eosinophilia in the bone marrow (BM) and increasing monocytosis, associated with what appeared to be
a variant t( 10;12)(q24;p13) translocation. We investigated
the TEL gene in both types of translocations with Southern
blotting and fluorescence in situ hybridization (FISH) analysis with cosmids specific for the 5’ end and the 3’ end of
the TEL gene. Moreover, 1Oq was further analyzed with a
panel of probes to better localize the breakpoint on 10q24.
LASSIFICATION OF myeloid leukemias thatshow
features of both myeloproliferative and myelodysplastic disorders have been the subject of intensive discussion
over the past few years.’” However, within this group of
disorders, cytogenetic analysis showed at least one recurrent
translocation, ie, a t(5;12)(q33;p13), among malignancies
classified as Ph-negative chronic myeloid leukemia, myelodysplastic syndrome (MDS), atypical chronic myelomonocytic leukemia (CMML), or chronic myeloproliferative disThis t(5;12) translocation, which has been recently
characterized at the molecular level, involves the plateletderived growth factor receptor-B (PDGFRB) gene at 5q33
and the TEL gene at 1 2 ~ 1 3which
,
is a novel member of the
ETS family.” The translocation results in expression of a
fusion transcript linking the 5’ helix-loop-helix (HLH) domain of the TEL gene to the transmembrane and tyrosine
kinase domains of PDGFRB.
From the Center for Human Genetics, University of Leuven, and
Department of Hematology, University of Louvain, Mont-Godinne,
Belgium; Institute of Hematology, University of Perugia, Italy; and
Department of Hematology, Hospital deSant Pau, Barcelona, Spain.
Submitted September 27, 1994; accepted January 3, 1995.
C.M. partially supported by Associazione Italiana per la Ricerca
sul Cancro.
Dedicated to Kazimierz Dux, MD, PhD, on
the occasion of his
80th birthday.
This text presents research results of the Belgian programme on
Interuniversity Poles of Attraction initiated by the Belgian State,
Prime Minister’s Ofice, Science Policy Programming.The scient$c
responsibility is assumed by its authors.
Address reprint requests to H . Van den Berghe, Centerfor Human
Genetics, Herestraat 49, B-3000 Leuven, Belgium.
in part by page
The publication costs of this article were defrayed
chargepayment. This article must thereforebeherebymarked
“advertisement” in accordclnce with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1995 by The American Society of Hematology.
0006-4971/95/8510-0027$3.00/0
2848
MATERIALS AND METHODS
Patients. The four patients involved in this study were collected
from three centers: Centre for Human Genetics (Leuven, Belgium),
case no. 1; Hospital de Sant Pau (Barcelona, Spain), case no. 2; and
the Institute of Hematology (Perugia, Italy), cases no. 3 and 4.Clinical and hematologic findings are summarized in Table 1.
Cytogenetics. Cytogenetic analyses from peripheral blood (PB)
and BM were performed after 3 days using synchronized cultures
without stimulation. R- andor G-chromosome banding was used.
Karyotypes are presented in accordance with ISCN.14
DNAanalysis.
The TEL cDNA wasamplified from a liver
cDNA sample using a 5’-CTCCAGAGAGCCCAGTGCCGAGT oligonucleotide as forward primer and a 5‘-TCCAGACGGTCTCGGCCACT oligonucleotide as reverse primer. The resulting 1.241-bp
cDNA that contains the complete coding sequence of TEL was
cloned into pGEM-3Z and was sequenced.
DNA was isolated from BM samples of patients no. 3 and 4 with
conventional methods. DNA (15pg) was digested with EcoRI or Pst
I, separated on an agarose gel, blotted onto a nylon membrane, and
probed with the complete TEL cDNA.
Cosmids were isolated from the Lawrence Livermore (Livermore.
CA) chromosome 12 library LL12NCO1 with the TEL cDNA as a
probe. High-density filters of the library were kindly grown byDr
E. Schoenmakers ( Department of Molecular Oncology, Center for
Human Genetics). Ten cosmids were isolated. Southern analysis of
the cosmids was performed with four fragments of the TEL cDNA
ranging from bp 79 to 371, bp 372 to 678, bp 679 to 1038, and bp
1039-1329 (numbering according to Golub et all3) and generated
Blood, Vol 85,No 10 (May 15). 1995: pp 2848-2852
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INVOLVEMENT OF TEL INMDS WITH ~ ( 5 ; 1 2 )OR ~(10;12)
with Xmn I, Sac I, and Acc I, respectively. Two cosmids were selected for further analysis, LL12NCOlN50F4 (cTEL5') and
LL12NCOlN148B6 (cTEL3'). Cycle sequencing using fluorescein
isothiocyanate end-labeled primers derived from the TEL cDNA
sequence and a commercially available sequencing kit (BRL, Gaithersburg, MD) on an automated laser fluorescence (ALF) sequencer
(Pharmacia, Uppsala, Sweden) confirmed the identity of the cosmids.
In situ hybridization was performed as previously de~cribed.'~
Probes cKTN206, cKTN420, and cKTN312 were kindly provided
by Dr J. Nishisho (Osaka University Medical School, Yamadaoka,
Japan); the LYT-10-specific probe PMd 1OPOO1, by Dr U.H.Weier
(University of California, Berkeley, CA); and D12S119, by Dr K.
Montgomery (AECOM, New York, NY). All other 12p cosmids
were isolated and ordered by FISH in OUT laboratory.16
FISH experiments were evaluated on a Zeiss Axioplan fluorescence microscope (Zeiss, Oberkochen, Germany) and a Leitz DMRB
(LDMRB) fluorescence microscope (E. Leitz Inc, Wetzlor, Germany) equipped with a cooled CCD camera (Photometrics, Stuttgart,
Germany) run by Imagenetics software (Imagenetics, Stuttgart, Germany). Eight to twenty-five informative chromosome spreads were
analyzed for each experiment.
RNA analysis. Total RNA was isolated from BM cells of patient
no. 3 by the guanidiniudacid phenol method. Total RNA (5pg) was
used for the synthesis of first-strand cDNA, primed with oligo(dT),
using Moloney murine leukemia virus reverse transcriptase (GIBCOBRL) in a volume of 20 pL. Five microliters of the reaction was
used for polymerase chain reaction (PCR) analysis. The TEW
PDGFRB fusion cDNA was amplified by nested PCR. For the TEL
gene the primers were 5'-CCTCCAGAGAGCCCAGTGCCGAGT
and 5'-TCAGGATGGAGGAAGACTCGA. For the PDGFRB gene
the primers described by Golub et a l l 3 were used. The PCR products
were cloned into Sm-I-digested pUC18, and 5 clones were sequenced on an automated sequencer (ALF; Pharmacia, Uppsala,
Sweden).
I
RESULTS
d
-c
s
U)
E
0
N
i
a
c
U)
S
E
l
2
Nature of the disease. Based on clinical and laboratory
findings (splenomegaly, monocytosis, eosinophilia, and absence of Ph chromosome and breakpoint cluster region rearrangement), three of the four cases (no. 1 to 3) presented
were diagnosed as CMML. The fourth case presented as
MDS with pancytopenia and only 2% of blasts in the BM
(RA). However, an increasing number of monocytes (20%)
was detected in the PB 20 months after diagnosis, when
blast cells increased to 25%. BM eosinophilia was also present from the beginning.
Cytogenetics. Cytogenetic analysis was performed at the
time of diagnosis in three cases (no. 2 to 4) and 2 years after
the first observation in patient no. 1. The t(5;12)(q33;p13)
was found as the sole structural abnormality in two patients;
one of them also had a t(5;12)-positive subclone with trisomy
21 (case no. 1). The karyotype from the third patient showed
a more complex rearrangement concerning chromosomes 6
and 16, in addition to the t(5;12). The fourth case was characterized by at(10;12)(q24;p13) as the sole chromosomal aberration detected in two consecutive BM samples, analyzed at
the time of RA and 2 years later, when evolution of the
disease to a CMML-like disorder was observed.
DNA and RNA analysis. The involvement of the TEL
gene in the t(5;12) and t(10;12) was studied by Southern
analysis and FISH with cosmids containing the 5' end or the
3' end of the TEL gene. To isolate these probes a TEL cDNA
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1
2850
was obtained by reverse transcription PCR and was cloned.
A 1,241-bp TEL cDNA was obtained containing the complete coding sequence. The sequence of this cDNA was identical to the published one.I3 The cDNA was used to screen
a chromosome 12 cosmid library. Ten cosmids were obtained
and characterized by Southern hybridization with restriction
fragments of the TEL cDNA. Two cosmids were selected
for further analysis. Clone cTEL5’ yielded a hybridization
signal at high stringency, with a cDNA fragment spanning
bp 79 to371 of the TEL sequence but yielded no signal with
any TEL probe derived downstream from bp 372 (results not
shown). Direct sequencing showed that cTEL5‘ contained a
TEL exon which ends at bp 187 of the TEL cDNA sequence,
and no sequence derived downstream from this exon. Thus,
cosmid TEL5‘ contains no sequences derived downstream
from the breakpoint in the t(5;12) case published by Golub
et al.I3 On the other hand, cosmid cTEL3’ showed a positive
signal with a probe derived from bp 1,039 to 1,329 of the
TEL cDNA and no signals with any probe derived upstream
from bp 1,039 (results not shown). Therefore, this probe
contains no sequences derived upstream from the published
breakpoint in TEL. Several cosmids containing TEL sequences between bp I87 and 1,039 were isolated. Because
these cosmids showed no overlap with either cTEL5’ or
cTEL3‘ and because they contain inserts of approximately
40 kb, the genomic sequence between both cosmids must be
at least 40 kb.
Southern hybridizations of genomic DNA isolated from a
BM sample of patients no. 3 and 4 and digested with EcoRI
and Pst I with the TEL cDNA did not show any rearranged
fragments. FISH with cosmid probes hybridizing to the chromosome region 12p was performed on leukemic cells from
all patients. Patient no. 4 was further investigated with cosmids covering 10q22.1 to 10q25.1 (Fig 1). FISH with TELspecific cosmids showed that cTEL3’ was present on the
normal chromosome 12p and the der( 12) all in analyzed
cases and was absent on the der(5) (patients no. 1 through
3) or the der(l0) (patient no. 4). The reverse was observed
with probe cTEL5’. Signals were present on the normal chromosome 12p and the der(5) for patients no. 1 through 3 or
the der(l0) for patient no. 4, but never on the der(l2) (Fig
2). Among the other 12p cosmids used, von Willebrand factor and PRBl hybridized to the der(5)t(5;12), whereas hybridization signals from the KRAS2, D12S 1 19,
and
D12S178 were foundon theder(12)t(5;12). Forchromosome
10, two cosmids cKTN420 (lOq22.1) and cKTN206
(10q22.3-q23.1)mapped proximal to the breakpoint. The
third probe, cKTN312 previously assigned by FISH to
lOq24.3-q25.1, as well as a probe for LYT- 10 mapped distal
to the breakpoint.
A fusion transcript of TEL and PDGFRB could be amplified from cDNA of patient no. 3 for which an RNA sample
was available. Sequencing of the resulting cDNA showed
that in this case the fusion occurred at the RNA level at
exactly the same position as reported by Golub et all3 for
their t(5;12) case.
DISCUSSION
We showed TEL gene involvement in four cases of MDSs
characterized by a t(5;12)(q33;p13) or a variant t( 10;12)
A
L
W TEW-
q
3
der151
3
WLODARSKA ET AL
p13
-1
TEW’
D12S178
D12S119
KRAS2
der(l2)
B
CKTN 312/LyT-10
D12S178
D12S119
KRAS2
cKTN 420
cKTN 206
TEW
PRBl
VWF
U
der110)
der112)
t(IO; 12)(q24;pl3)
Fig 1. Graphical presentation of (A) t(5;12) and (B)t(10;12) translocations. Probes used in FISH experiments and their positions in relation to breakpoints on chromosome 5, 10, and l 2 are indicated.
(q24;p13). In three cases diagnosis was compatible with
CMML, whereas the fourth case with the cytogenetic variant
t(10;12) had a RA,which later evolved to a CMML-like
disorder with eosinophilia and monocytosis. The 5;12 translocation was described for the first time by Keene et al’ in
two patients characterized by eosinophilia and 12p abnormalities, diagnosed as eosinophilic leukemia and Ph-negative CML. An additional case was reported by Srivastava et
a19 in which CMML was characterized by overexpression of
the KRAS2 oncogene, assigned to 1 2 ~ 1 2Six
. other cases of
atypical CML, CMML with eosinophilia or myeloproliferative disorder with dyserythropoiesis and eosinophilia, and
t(5;12) have been published by Berkowicz et al,”’ Martiat et
a1: Wessels et
and Baranger et al.” It waspostulated
that the translocation represents a clinical entity with features
of both CML and CMML” and eosinophilia.” However, an
additional observation was published by Lerzaet all’ as a
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INVOLVEMENT OF TEL IN MDS WITH ~(5;12)OR T(10;12)
2851
t(5;12)
r'
4
L
'4
'r"
Fig 2. FISH with coomids specific for the 5' end (cTEL5') and the 3' end (cTEL3') of TEL gene performed in t(5;121andt(10;12)cases.
Chromosome 12 anda der(12) are indicatedby arrows; a der(5) and der(10) are indicated
by arrowheads.
The t(5;12) was recently cloned by Golub
et al." The investicase of RA with monocytosis and fibrosis. Altogether, data
gators showed that the translocation results in expression of a
from the literature, from our patients no. 1, 2, and 3, and
fusion transcript between a novel gene at 12~13,called TEL
the clinical evolution of case
no. 4 allow us to conclude that
(for translocation,ets, leukemia), whichis a member of theETS
themalignantdisorderassociatedwithastructuralrearrangement on 12p13/TEL gene is characterized by a high family, and the PDGFRBgeneat5q33.TheTELPDGFRB
number of monocytes (more than
8% of the differential count fusion includes the 5' HLH domain of TEL and the transmembrane and tyrosine
kinase domains of PDGFRB. Themechanism
in PB) and BM eosinophilia (more than 5% in BM) and is
consistent with diagnosis of CMML
in the majority of cases. of transformation by the TELPDGFRB fusion is not known.
Cytogenetically the 1 2 ~ 1 3involvement is usually because
However, it is of interest that the recipmcal fusion transcript
of a 5;12 translocation. Moreover,for the first time a cytoge-containing the TEL, DNA-binding domain is not expressed in
leukemic cells; thmfore, the chimeric gene shows mainly the
netic variant t(10;12)(q%;p13) translocation is shown.
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
WLODARSKA ET AL
2852
some-negative chronic myelogenous leukemia and chronic myelooncogenic potential of PDGFW3. Our experiments with a TEL
monocytic
leukemia. Hematol Oncol Clin North Am 4:389, 1990
cDNA p
b
e could not show a rearrangementon Southern blot4. Martiat P, Michaux JL, Rodhain J: Philadelphia-Negative
ting. Indeed,although Golubet all3mentioned detection of TEL
(Ph-) chronic myeloid leukemia (CML): Comparison with Ph+ CML
rearrangement by Southern blotting and ribonuclease assays, it
and chronic myelomonocytic leukemia. Blood 78:205, 1991
is not clear whether they used genomic or cDNA p b e s for
5. Mecucci C, Van den Berghe H: Cytogenetics, in Koeffler HP
the former analysis. Our results suggest that the brealrpoint on
(ed): Myelodysplastic Syndromes. Philadelphia, PA, Saunders, 1992,
chromosome 12 may occur in an intron sequence of the TEL
p 523
6. Michaux JL, Martiat Ph: Chronic myelomonocytic leukaemia
gene not detected by the applied combination of restriction en(CMML) - A myelodysplastic or myeloproliferative syndrome? Leuk
zymes and the "EL cDNA. The large genomicsize of the "EL
gene supportsthis hypothesis. In case no. 3, however, sequencingLymphoma 9:35, 1993
7. Dickstein JI, Vardiman JW: Issues in the pathology and diagof the fusion cDNA showedthat exactly the samefragments of
nosis of the chronic myeloproliferative disorders and the myelodysthe TEL and PDGFRE3 genes were fusedas described by Golub
plastic syndromes. Hematol Path01 99:513, 1993
et al,13 further supporting the hypothesis that in these cases the
8. Keene P, Mendelow B, Pinto MR, Bezwoda W, MacDougall
HLH domain of TEL might be of functional importance.
L, Falkson G, Ruff P, Bernstein R: Abnormalities of chromosome
1 2 ~ 1 and
3 malignant proliferation of eosinophils: a nonrandom assoThe FISH investigations in this study and the cDNA analysis
ciation. Br J Haematol 67:25, 1987
of one case definitelyp v e d that thebmkpints in both t(5;12)
9. Srivastava A, Boswell HS, Heerema NA, Nahreini P, Lauer
and t(10;12) occurred within the TEL gene. Indeed, the 3' end
RC, Antony AC, Hoffman R, Tricot G: KRAS2 oncogene overexof the TEL gene is maintained on the d e ~ l 2 )chromosome,
pression in myelodysplastic syndrome with translocation 5;12. Canwhereas the 5' end of E L is translocated to the der(5) or the
cer Genet Cytogenet 35:61, 1988
der(l0) in both the t(5;12) and the t(10;12) cases, respectively
10. Berkowicz M, Rosner E, Rechavi G, Mamon Z, Neuman Y,
(Fig 2). 'Ihus, hematologic features, karyotypic results, and moBen-Bassat I, Ramot B: Atypical chronic myelomonocytic leukemia
with eosinophilia and translocation (5;12). A new association? Canlecular data are in keeping with the definition
of 1012 translocation as a variantof t(5; 12). The involvement
of another hypotheti- cer Genet Cytogenet 51:277, 1991
11. Lerza R, Castello G, Sessarego M, Cavallini D, Pannacciulli
calgenewithin an intron of TEL inthe case with t(1012)
I: Myelodysplastic syndrome associated with increased bone marrow
appears to be extremely unlikely. These results also show the
fibrosis and translocation (5;12)(q33;p12.3). Br J Haematol 82:476,
usefulness of isolated TEL cosmids as p b e s for the analysis
1992
of the involvement of TEL gene in MDS. In addition, data are
12. Baranger L, Szapiro N, Gardais J, Hillon J, Derre J, Francois
CoIlSistent with apte1-5'TEG3'TEknt orientation for the TEL
S, Blanchet 0, Boasson M, Berger R: Translocation t(5;12)(q3133;p12-p13): A non random translocation associated with a myeloid
geneonchromosome12andaqter-SPDGFW3-3'PDGFRBdisorder with eosinophilia. Br J Haematol 88:343, 1994
cent orientation for the FDGFRB gene on chromosome 5 .
13. Golub TR, Barker GF, Lovett M, Gilliland G: Fusionof PDGF
Further analysis of the t(5;12) and a t(lQ12) with a panel of
receptor p to a novel ets-like gene, rel, in chronicmyelomonocytic
12pspecific cosmids allowed us to determine the positionof the
leukemia with t(5;12) chromosomal translocation. Cell 77:307, 1994
brealrpoint, as well as of the TEL gene, between D12S178 and
14. Mitelman F (4):ISCN: Guidelines for Cancer Cytogenetics,
P M 1 lociat 12~13.Withrespect to chromosome10, FISH
Supplement to an International System for Human Genetic Nomenanalysis showed that the breakpoint occurred in a region
flanked
clature. Basel, Switzerland, Karger, 1991
15. Wlodarska I, Mecucci C, Vandenberghe E, De Wolf-Peeters
bycKTN206and cKTN312LYT-10at 1Oq24.Althoughthe
lOq24 chromosome region carries some genes that may play an C, Thomas J, Hilliker C, Schoenmakers E, Stul M, Marynen P,
important role in leukemogenesis and lymphomagenesis (namely Cassiman JJ, Van den Berghe H Dup(l2)(ql3"qter) in two t(14;18)negative follicular B-non-Hodgkin's lymphomas. Genes ChroTcL3 (HOXlI),'* LYT-lO,I9 and APO-liFASZo), no recurrent
mosom Cancer 4:302, 1992
associations of 1Oq24 chromosomal abnormalities with myeloid
16. Chaffanet M, Baens M, Aerssens J, Schoenmakers E, Cassidisorders have been reported before.
man JJ, Marynen P: Mapping of an ordered set of 14 cosmids to
human chromosome 12p by two-color in situ hybridization. CytoIn summary, the findings discussed here show that the TEL
genet Cell Genet 69:27, 1995
gene may be activated not only by fusion with the PDGFRE3
17. Wessels J W , Fibbe WE, van der Keur D, Landegent JE, van
gene on chromosome 5q33.1, but also by unknown sequences
der Plas DC, den Ottolander GJ, Roozendaal KJ, Beverstock GC:
on 1Oq24, located upstreamto LYT-10. Involvement of theTEL
t(5;12)(q31;p12). A clinical entity with features of bothmyeloid
in pathogenesis of h4DS may be easily analyzed by FlSH with
leukemia and chronic myelomonocytic leukemia. Cancer Genet Cycosmids containing the 5' end and 3' end of TEL.
togenet 65:7, 1993
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From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
1995 85: 2848-2852
TEL gene is involved in myelodysplastic syndromes with either the
typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13)
I Wlodarska, C Mecucci, P Marynen, C Guo, D Franckx, R La Starza, A Aventin, A Bosly, MF
Martelli and JJ Cassiman
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