Download Rearrangements in the Human T-Cell-Receptor Â

(CANCER RESEARCH 50. 6171-6175. October I. I990|
Rearrangements in the Human T-Cell-Receptor «-ChainLocus in Patients with
Adult T-Cell Leukemia Carrying Translocations Involving Chromosome 14qll'
Masaharu Isobe, Naoki Sadamori, Giadomenico Russo, Shoichi Shimizu, Shunji Yamamori, Takahiro Itoyama,
Yasuaki Yamada, Shuichi Ikeda, Michito Ichimaru, Jacob Kagan, and Carlo M. Croce2
Department of Patho-biochemistry. Research Institute for Oriental Medicines, Toyama Medical and Pharmaceutical L'nirersily, Toyama 930-01, Japan /M. I.];
Department of Hematology, Atomic Disease Institute, Nagasaki L'nÃ-versÃ-ly,
School of Medicine, Nagasaki 852, Japan ¡N.S.. T. I., Y. Y., S. /., M. /./,- Raggio-ltalgene,
Pomezia, Roma, Italy [G. R.¡;Mitsubishi Yuka Bio-Clinical Laboratories, Inc., Tokyo 174, Japan ¡S.S., S. Y.J; and Fels Institute for Cancer Research and Molecular
Biology, Temple University, Philadelphia, Pennsylvania 19140 ¡J.A'., C. M. C.J
a very extensive panel of probes to look for the rearrangements
in the TCR a/5 locus. This locus contains an extra large J«
We describe 5 cases of adult T-cell leukemia (ATL) carrying translo
region
(21) and a complex TCR «locus. Using these probes we
cations at chromosome 14ql 1, where the genes for a- and ¿-chainsof the
T-cell receptor (TCR a/6) reside (Croce et al., 1985; Isobe et al., 1988). found deletions of the TCR ôlocus in all cases of ATL. And
we were also able to demonstrate rearrangements in the J«
Since the TCR aßlocus is the region where several types of chromosome
translocations occur in T-cell tumors, rearrangements of the TCR aß locus in DNA from 5 ATL patients.
ABSTRACT
locus in those ATL cases were studied as a first step to characterize
these translocations at the molecular level. For this purpose we have
generated an extensive series of probes to define the specificity and the
diversity of rearrangement occurring at the widely spanned Jor-Ca locus
and the complex D6-JÕ-C6-VÕ2
locus. Using a set of probes, we have
found the deletion of the TCR 6 locus in all ATL cases, and at least 2
rearrangements in the J6 locus in each case of ATL. It is possible that
translocations in the TCR a locus may be involved in ATL.
INTRODUCTION
ATL3 is defined on the basis of the clinical picture, distinct
morphology of the abnormal lymphocytes, and T-cell markers.
Particularly close association of HTLV-I infection with leukemogenesis of ATL has often been reported by a number of
serological and epidemiológica! studies (1,2). However, lack of
oncogenes in the HTLV-I genome (3) and the occurrence of
disease in a very small proportion (0.01-0.02%) of HTLV-Iinfected individuals (1) imply that additional genetic changes
may be required for the onset of the disease. Nonrandom
chromosome translocations are a nearly constant feature of
human leukemias and lymphomas. In 1985, we reported re
arrangements of 14ql 1 to be specific for the acute type of ATL
(4), which was confirmed by others (5). To this region, we have
mapped the loci for the TCR a/o gene (6, 7). The chromosomal
region at band 14ql 1 was also found to be rearranged in other
types of T-cell malignancies (8). The molecular involvement of
the TCR a/o gene in a number of translocations such as t(8;14)
(q24;q 11) (7, 9), t( 14; 14) (q 11;q32) ( 10, 11), inv( 14) (q 11q32)
(11-14), t(ll;14) (pl3;qll) (15, 16), t(ll;14) (pl5;qll) (17),
t( 10; 14) (q23;q 11) ( 18), and t( 1; 14) (p32;q 11) ( 19, 20) has been
described in the HTLV-I-negative T-cell malignancies. Those
breakpoints specifically occur within the J or the D region of
the TCR a/ó locus. However, there is no report of the direct
involvement of the TCR «/ólocus in the patient with ATL
which is positive for the HTLV-I.As a first step to determine
the location of translocation breakpoints in ATL, we prepared
Received 1/26/90; accepted 7/2/90.
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.
' This work was supported in part by a Grant-in-Aid for Cancer Research from
the Ministry of Education, Science, and Culture, Japan.
2 To whom requests for reprints should be addressed, at Fels Institute for
Cancer Research and Molecular Biology, Temple University School of Medicine.
3420 North Broad Street. Philadelphia. PA 19140.
3The abbreviations used are: ATL, adult T-cell leukemia/lymphoma; HTLVI, human T-cell leukemia virus I; TCR, T-cell receptor; TEA, T-cell early «;J
(D), joining (diversity) region of the TCR H/ÕI
locus.
MATERIALS
AND METHODS
Cytogenetic Analysis. Samples for the cytogenetic studies were ob
tained from the peripheral blood of ATL patients at the time of
diagnosis. Mononuclear cells separated by centrifugation over FicollHypaque gradients were cultured in RPMI 1640 medium supplemented
with 10% fetal calf serum without any mitogens. The cells were har
vested after 1 or 20 h. Colcemid was added 1 or 2 h before harvesting.
In each specimen, at least 15 metaphases were analyzed using G- and
Q-banding techniques.
Probes. Probes for the TCR a/o locus were generated from genomic
clones (7, 10) and subcloned into pBluescript SK(-) for the probes
pMll, pMI2, pMI4-6, pMI8-13, ppMIlS, and pMI19, pucl9 for those
of pMI3 and pMM6, plBI25 for that of pMI14, and M13mpl8 for
those of pMI17 and plVIIlS. The location of probes and the cloning
sites of each fragment are indicated in Fig. 2.
Analysis of DNA. DNA was extracted from peripheral lymphocytes
and digested with one of the restriction enzymes, BamHl, Sstl. or
EcoR\, according to the suppliers' recommendations. The cut DNA
was separated by electrophoresis on 0.6% agarose gel. transferred to
nitrocellulose filter according to the methods described by Southern
(22), and hybridized to 32P-labeled genomic J«/5 probes. Re
arrangement was scored by loss of germ line band or by the appearance
of prominent new bands.
RESULTS
Cytogenetical Analysis of ATL Cases. Abnormal clones found
in 5 patients with ATL are shown in Table 1. The modal
chromosome numbers ranged from 46-48. All 5 patients had
either an inversion or a reciprocal translocation involving chro
mosome 14, band qll, such as inv(14) (qll;q32) in case 1,
t(12;14)(q24;qll)
incase 2, t(14;14) (ql I;q32) in cases 3 and
4, and der(14) t(14;3) (qll;ql2) in case 5. Those chromosome
abnormalities involving 14ql 1 are shown in Fig. 1. It has been
shown that the loci for TCR a/o reside in chromosomal region
14ql 1 where several chromosomal translocations are found to
occur in T-cell malignancies (7, 9-20). On the other hand, in
our cases there was no evidence of abnormalities of chromo
some 7 where the loci for the /3- and ^-chains of TCR are
located, at bands 7q35 and 7pl4, respectively (23, 24).
Probes for TCR a/6 Locus. As shown in Fig. 2, we have
developed 20 DNA probes to look for the rearrangement of the
D5-Ja-C(5/Jtt-Ctt locus including 3 probes (pMll 1, pMI12, and
pMI19) which have been reported previously (7, 10). Since the
deletions or rearrangements in the TCR locus usually occur 5'
to either the D or the J segments, we prepared probes that
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TCR-c. REARRANGEMENTS
IN ADULT T-CELL LEUKEMIA
arrangement in the TCR a locus is shown in Table 3. Both
alÃ-elesof the TCR ¿locus were deleted in all cases of ATLs
(Table 3, Fig. 3). Although there is a faint band of the germ
line Ja band detected with pMI19 in cases I, 2, and 3, these
bands were probably due to contamination of normal cells,
since cytogenetic analysis showed that only 81, 56, and 35% of
cells were found to be leukemic cells in patient's 1, 2, and 3,
•lÃ
Case 1
14
respectively (Table 1). Moreover, the intensity of those bands
compared with the human placental DNA as a germ line control
were about 10, 30, and 50% in cases 1, 2, and 3, respectively
(Fig. 3). As shown in Table 3, we found at least two re
arrangements of the a locus in each cases of ATL. Fig. 4 depicts
an example of rearrangement detected in cases 3, 4, and 5 using
a pMI3 probe. ÄamHI-digested DNA from cases 3 and 4
showed a rearranged band of 6.3 and 13 kilobases, respectively,
as well as a 5.4-kilobase germ line band. Ssfl-digested DNA
from case 5 shows 2 rearranged bands (one 7.5-kilobase band
and another 13-kilobase faint band) as well as a faint 8.4kilobase germ line band which probably derived from the con
tamination with normal cells. We found the same re
arrangements in case 5 using the pMI2 probe, but the intensity
of two bands was almost identical. However, no rearrangement
was detected by using the pMI2 probe when the DNA from
case 5 was digested by BamHl (Fig. 2). Thus, one of the
rearrangements, corresponding to the 13-kilobase band, took
place within, but near the 3' end of, the pMI3 probe. Another
rearrangement, corresponding to the 7.5-kilobase band, took
place between the pMI4 and pMI3 probes, since we did not
detect any rearrangement band using a pMI4 probe. The other
rearrangements in cases 3 and 4 were found by using a pHO.6
probe. The size of the rearranged EcoRl fragments was 5.5 and
1.8 kilobases, respectively. Two rearranged BamHl fragments
of 4.7 and 4.5 kilobases were found in case 1 using pMIlO and
pMI13 probes, respectively. In case 2 there are two rearranged
EcoRl fragments detected by pMI8 and pMIlO. The sizes of
the fragments were 13 and 13.5 kilobases, respectively.
Case 2
14
Case 4
14
Case 5
Fig. 1. Four types of 14qll anomaly. inv(14) (qllq32), ill 2:141 (q24;qll).
Ml4:l4i (qll:q32). and der(14)t(14;3) (ql I:ql2) in cases 1, 2, 4. and 5. respec
tively. Arrows, positions of chromosomal breakpoint.
DISCUSSION
contained the most 3' region of the genomic fragments digested
with either BamHl or EcoRl in the TCR a/6 locus in order not
to miss the rearrangement (Fig. 2). The germ line restriction
fragments obtained with those probes are shown in Table 2. A
panel of those probes made it possible to look for most of the
rearrangements occurring 5' to each D or J segment as well as
in the Vi52 region, which is located between O or Ja in the
TCR a/o locus (26), using a combination of BamHl, EcoRl,
and Sstl digests of the DN A samples.
TCR a/6 Rearrangements in ATLs. A summary of the re
The TCR a/a locus has two prominent features compared to
other TCR loci. The first is the presence of an extra large Ja
region which spans about 73 kilobases from the 5' end of Ca
region (Fig. 1). The second is the presence of the TCR o locus
inside the TCR a locus. This large Ja region has been making
it difficult to find rearrangements in the TCR a/a locus. Our
panel of probes described in this paper proved to be very useful
in localizing the rearrangements in the D6-C6/J«-Co locus in
DNA from patients' peripheral blood. This approach, therefore,
will provide a powerful method to diagnose the clonality of the
Table 1 Hematological cytogenic data forßrepatients with adult T-cell leukemia
Patient
Case
1
Age (yr)
65
Sex
M
2
61
F
Leukocyte
count( el !
50.600
8,500
Leukemic
cells (%)
81
56
Clonal karyotype
47. X, -Y, +3, +mar. del (6) (p23). inv (14) (ql Iq32)
48, XX. +4, +18, -19, -21, -22, +3mar. t (3;10) (ql I;ql2). t (I2;14)
(q24;qll)
3
65
F
51.600
35
48. X, -X. +2. -4, -(-der (4) t (4;?) (p16:?), del (5) (ql3), t (l4;14)
(ql I;q32), del (14) (ql Iql3), +2mar
4
57
F
183,500
91
46. X. -X, -10, -12, +14. -17, +3mar, t (14;14) (ql I;q32)
5
40
M
84,850
86
46. XY.-14,
dup (I) (q2lq32). del (3) (ql2). del (5) (pl3),-(-der (14) t
6172
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TCR-,, REARRANGEMENTS
IN ADULT T-CELL LEUKEMIA
«J3
«•
CM—HtObO—H—
—
o1o
O—H
1—1
BS¿|!
ss!"
IHH
M"*»B
SII
SI/1 S
i SS
i i SU
il! il1
X [X»
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l *
•!!•IlM
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1o1—*ëD
Ȕ,s
„
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Si1
E E E
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*W !HHH.
EE*E
* ,
X
E
PMII7i
1100
i
,
H
XX
(1
Kg
EEEE
:¡iMill
B E
E
B•
UH
1a
HB"BKV(
B
B
_BpMI15
SpMI9H
l70
HS
B
li i,H
EpMI7
B E
,
H,
H
sÃ-fs?!l'f
Ã-£l!'i?-u?isss
i
l¡I' '
pMIIP
B
i50KilobasesS
1
!40B
pHOEl
l30
60E
BPMI2
B H
HPMI4B
E
pMIB1
i
UT—
1 23
m
—i—a—
1—Co t-l
t\
HHB
pMIEHHI
EpMIIOi
pMIt31
i80B
1
0-4-
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EpMIllE
B
90E
o
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;IH.I:B
pMMB
pMI16E
1110B
1
,H
o— a
1—a—
i—o—
1—a1
—a—
1a—
11li11Kf II11B
8•
E
BpMI19i
1
BpMI31
pMI5e
i
1IO
20B
!
1
1
0
-IO
Fig. 2. Genomie map of the human Cô-J5-O-VU2/J«-C«locus showing position of probes used in this study. The restriction map was deduced from analysis of
overlapping recombinant cosmid and \ clones obtained from various genomic libraries (7, 10). Restriction sites are given for /¡«ml
II (fi), EcoRl (E), ///m/lll (//),
Sstl (S), and Xba\ (A"). Top line, black boxes, structural genes. Location of Do, J5, Co, V<52,TEA, pseudo-J« (<t>Ja),}n, and C«are Refs. 9-15, 21 and 25-30. *,
polymorphic restriction sites. Solid bars, 20 probes generated from genomic DNA clones. The cloning sites of each fragment are indicated on each of the probes. +,
the cloning site which was generated during cloning steps.
Table 2 DNA probes and restriction enzymes used
Probea,
makes a noncoding RNA (27). The expression of TEA and of
pseudo-J« (0Jtt), which is located just 3' to the TEA, is pos
line frag
enzymeSstllt,l ments
(kilobases)5.2
tulated to be important for the deletion of the TCR a locus
together with the <5Recregion, which is located between V51
USstlBamHlSst\BamHlSstlBamHlEcoRlBamHlSstlEcoRlBamHlSstlEcoRlBamHlEcoRlEcoRlBamHlEcoRlBamHlEcoRlBamHlBamHlBamHlBamHlBamHlBamHlBamHlBamHlBam
in]
and Do, before the TCR «rearrangement begins (28).
5.25.08.45.48.45.42.4+
+ 2.3 +
Use of immunoglobulin and T-cell receptor genes for study
of clonality and lineage in lymphoproliferative disorders is well
established. Although these molecular probes are valuable in
the establishment of clonality, their usefulness in defining lin
1.43.35.1
eage requires careful consideration. For example, it has recently
been shown that the TCR 5 locus is often rearranged in B+8.44.84.0
lineage acute lymphocytic leukemia as well as in "prethymic"
3.68.2
+
T-cell
acute lymphocytic leukemia (31). Nevertheless, there is
5.14.53.83.08.23.6
+
a hierarchy of frequency of rearrangements, TCR 5 > TCR 7 >
TCR 0+0, which reflects the presumed ontogenetic timing of
such rearrangements in normal T-cell development (TCR ô
3.88.26.0
+
before y before o and /i). From this point of view, it is reasonable
to have a biallelic deletion of the TCR ¿locus and re
3.64.811.6
+
arrangements of the J«locus in ATL since the HTLV-I virus
6.011.64.4
+ 3.2 +
can only infect CD4-positive T-cells. In fact, all of the ATL
cases we have reported in this paper had CD4-positive and
11.64.41.69.414.014.014.015.3Ref.10107
+
CDS-negative phenotypes (data not shown).
The direct involvement of the TCR a/6 locus in the (8; 14)
JaVi2J63,
<t>
Ja,
translocations involving c-myc oncogenes has been demon
CiD63,
strated (7, 20, 32). As a result of the translocation, the Ja-Ca
or J<5-O-J«-Ca region is moved to a region 3' to the involved
JJl, Ji2ClonepMIlpMI2pMI3pMI4pMI5pM16pH0.6pM17pMI8pMI9pMIIOpMIllpMll2pMII3pMH4pMH5pMIlópM117pMIISI.Mll'iRestriction
c-myc oncogene on the 8q+ chromosome causing a transcriptional deregulation of the involved c-myc gene (32). These
T-cell malignancies and to determine the sites of chromosomal
findings suggest that the locus for the <•
or ¿-chainmay be
involved in deregulation of putative oncogenes in T-cell malig
translocations in T cell neoplasm.
It is worthwhile to mention that probe pMIIS includes a nancies, similar to the role of the human immunoglobulin loci
in c-myc and bcl-2 deregulation in Burkitt lymphoma and in
region named TEA which is transcribed in fetal thymocytes
JaTEA,
2.24.08.4
+
Table 3 Patterns of T-cell receptor a-gene rearrangements
Patient1
R/D
G/R
D/D
D/D
D/D
D/D
D/D
G/D
G/G
G/G
G/G
D/D
D/D
D/D
D/D
D/D
D/D
R/D
G/D
G/R
D/D
D/D
G/G
D/D
D/D
D/D
D/D
D/D
D/D
R/D
D/D
D/D
G/D
G/R
G/G
D/DpMI13Rl/D
D/DpMI12Rl/D
D/DpMIllG/D
D/DpMIIOG/R
D/DpHO.6G/G
5pMI19D/D"
D/DpMIISD/D
D/DpMI9G/G
D/DPMI8G/G
D/DpMISG/G
D/DpMI3G/G
R/RpMIlG/GG/G
G/G
'G, germ line; D. deletion; R. rearrangement: Rl. the same rearrangement detected by two consecutive probes, pMH3 and pMll2.
2
34
6173
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TCR-Ã-vREARRANGEMENTS
(Kb)
15.3-
IN ADULT T-CELL LEUKEMIA
G 1 2 345
TCR loci, like the Jß-Cß
and the Ja-C«loci, have moved to the
so-called tcl-1 region at chromosome 14q32.1, centromeric to
the IgH locus (36). From this point of view it is very important
to clarify whether the J«rearrangements found in ATL cases
are actually involved in translocations. For this purpose we are
presently cloning the rearranged «loci to establish whether
they are involved in the translocations observed by cytogenetic
analysis. This seems to be likely since in all of the previously
described translocations in B- and T-cell malignancies the translocation involves the unproductively rearranged immunoglobulin or TCR gene (9, 35). Furthermore, it will be important to
establish whether there is a relationship between breakpoints at
chromosome 14q32 found in HTLV-I-positive and HTLVnegative T-cell malignancies.
ACKNOWLEDGMENTS
We thank Nobuyuki Kurosawa, Hideki Nagumo, and Donna Papsun
for their excellent technical assistance and Dr. Zen-ichi Ogita for
fruitful discussions.
BamHI
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Fig. 3. Southern blot analysis of Do and J¿genes in ATL cells. Abscissa,
patient numbers; lane G, control DNA from human placenta, linn lines, germ
line band sizes [in kilobases (A'A)|.DNA samples have been digested with AVmilII
restriction enzyme and hybridized with pMI19 probe.
G 3 4
(Kb)
G 5
(Kb)
8.4-
5.4-*»«»
BamHI
Sstl
Fig. 4. Representative rearrangement pattern of the TCR «gene in ATL cells.
Abscissa, patient numbers; lane G, human placenta! DNA as a germ line control.
DNA samples have been digested with restriction enzymes and hybridized with a
pMI3 probe as indicated. Thin lines near G, germ line band sizes [in kilobases
(Kb)].
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TCR-,. REARRANGEMENTS IN ADULT T-CELL LEUKEMIA
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Downloaded from cancerres.aacrjournals.org on June 18, 2017. © 1990 American Association for Cancer Research.
Rearrangements in the Human T-Cell-Receptor α-Chain Locus in
Patients with Adult T-Cell Leukemia Carrying Translocations
Involving Chromosome 14q11
Masaharu Isobe, Naoki Sadamori, Giadomenico Russo, et al.
Cancer Res 1990;50:6171-6175.
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