1. No category

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Expression of ~ 1 3 ~ Is
~ 'Restricted
~ '
To Mature T - c e l l Proliferations With
t(X; 14) Translocations
By Ali Madani, Valerie Choukroun, Jean Soulier, Valere Cacheux, Jean-FranFois Claisse, FranGoise Valensi,
Sylvie Daliphard, Bruno Cazin, Vincent Levy, Veronique Leblond, Marie-Therese Daniel, FranGois Sigaux,
and Marc-Henri Stern
T-cell prolymphocytic leukemia (T-PLL), a rare form of mature T-cell leukemias, and ataxia telangiectasia clonal proliferation, a related condition occurring in patients suffering
from ataxia telangiectasia, have been associated t o translocations involving the 14q32.1 or Xq28 regions, where are
located the TCLl and MTCP7 putative oncogenes, respectively. The M E P 7 gene is involved in the t(X;14)(q28;qll)
translocation associated with these T-cell proliferations. Alternative splicing generates type A and B transcripts that
potentially encode two entirely distinct proteins: type A
transcripts code for a small mitochondrial protein, ~ 8 ~ ~
and type B transcripts, containing an additional open reading frame, may code for a 107 amino-acid protein, ~ 1 3 ~ ' " .
The recently cloned TCLl gene, also involved in translocations and inversions associated with T-cell proliferations,
codes for a 14-kD protein that displays significant homology
with ~ 1 3 ~ We
~ " have
.
generated rabbit antisera against
this putative ~ 1 3 ~ protein
' ~ ' and screened for expression
of p13Mrcp' normal lymphoid tissues and 33 cases of immature and mature lymphoid T-cell proliferations, using a sensitive Western blot assay. We also investigated the MTCPl
locus configuration by Southern blot analysis. The ~ 1 3 ~ ' '
protein was detected in the three T-cell proliferations with
MTCP7 rearrangements because of t(X; 14) translocations,
but neither in normal resting and activated lymphocytes nor
"in the
. other T-cell leukemias. Our data support the hypothesis that p13Mrcp' and ~ 1 4 " ~form
'
a new protein family that
plays a key role in the pathogenesis of T-PLL and related
conditions.
0 7996 by The American Society of Hematology.
T
from hemophilic patients with Xq28 deletions including the MTCPI
-CELL PROLYMPHOCYTIC leukemia (T-PLL) is a
gene." Peripheral blood lymphocytes (PBL) were obtained from
rare form of mature T-cell proliferations that has been
normal individuals. T and B lymphocytes were separated from a
associated with translocations involving the 14q32.1 renormal spleen by 2-aminoethylisothiuronium bromide-treated sheep
gion'.* and to a lesser extent the Xq28
A preinvared blood cells rosetting. Leukemic samples were obtained from
sive stage of T-PLL, named Ataxia Telangiectasia Clonal
our cryopreserved leukemic cell collection, except for some T-PLL
Proliferation (ATCP), has been described in the cancer-prone
samples which were obtained from different French hematologic
genetic disease ataxia telangiecta~ia.~-''
The presence of
centers. The cytological diagnosis was reviewed by a member of
identical translocations in ATCPs and in T-PLLs supports
the French-American-British (FAB) Committee (M-TD). Short-term
the view that these translocations play a role in the early
cell culture from patient Dol blood sample was also analyzed. A
stages of the disease. On this basis, the MTCPl gene was
proportion of 230% of clonal cells in the Dol cell culture was
estimated by Southern blot technique (data not shown).
identified by its involvement in the t(X; 14)(q28;qll) transProduction of antisera againstpl.fMTCP'.The 321 nt open readl ~ c a t i o n . ' ~So
. ' ~far, the five t(X; 14) breakpoints cloned ocing
frame of the type B MTCPl transcript (orfl07) was amplified
curred 5' to or within the MTCPl
The MTCPl
by the polymerase chain reaction (PCR) using the following primers:
gene encodes for several mRNAs generated by alternative
5'-CCGGATCCAAAGGAGCATATCTTCG-3'
and 5'-CGGGGAsplicing. The 1.0- to 1.2-kb type A transcripts code for an
TCCATGGCAGGAGAGGAT-3'. The PCR product was cloned into
unusually small protein of 8 kD ( ~ 8 ~ ~ ' " that
) ' ~ is located
the BamHI site of the pGEX2T vector leading to an in frame fusion
in the mitochondria.16 Type A transcript^'^-'^ and p8MTCP'15 with the GST gene (pGEX2T-orfl07). The sequence of the construct
are highly expressed in T-cell proliferations with t(X; 14).
However, we have described another splicing type of
MTCPl transcripts (type BI), composed of four additional
From the Laboratoire d'Hdmatologie Moldculaire, Hbpital Saint
exons, that contains an additional 321 nt open reading frame
Louis, Paris; Unite' de Cytogindtique, Hbpital Robert Debrd, Paris:
potentially coding for an entirely different protein of 13
Laboratoire d'Himatologie, Amiens; Service d 'Hdmatologie BiolokD (p13MTcp').13
Using Northern blot analysis, this class of
gique, Hbpital Necker, Paris: Laboratoire Central d'Hdmatologie,
Reims; Service des Maladies du Sang, Lille; Service d'Hdmatologie,
mRNAs was found at minute levels in tissues analyzed so
H&el-Dieu, Paris: and the Dkpartement d'Hdmatologie, Hbpital
far.13
Pitid-Salpe^tridre,Paris, France.
The recent cloning of TCLI, the candidate 14q32.1 oncoSubmitted July 12, 1995: accepted October 2, 1995.
gene, showed at the protein level an unquestionable homolSupported by l'INSERM, la Fondation contre la Leucdmie, le
ogy with p13MTcp'.17.'s
Both TCLI and MTCPI gene products
Comiti de Paris de la Ligue Nationale Contre le Cancer, la Fondado not share homology with other known sequences and thus
tion pour la Recherche Midicale, and la Direction de la Recherche
constitute a new gene family. Rearrangements in the vicinity
et des Etudes Doctorales.
of these genes observed in T-PLLs and related T-cell prolifAddress reprint requests to Marc-Henri Stem, MD, PhD Laboraerations strongly advocate for their roles in the pathogenesis
toire d'Hdmatologie Moldculaire, Centre Hayem, Hbpital Saint
of T-PLL.
Louis, 75475 Paris Cedex IO, France.
This homology between ~ 1 4 ~ and
' ~ ' the putative ~ 1 3 ~ ~ " ' The publication costs of this article were defrayed in part by page
protein led us to analyze ~ 1 3 ~ ~ ' expression
''
in T-PLLs.
charge payment. This article must therefore be hereby marked
MATERIALS AND METHODS
Cells. Cell lines used: cos-7 is a monkey SV40 transformed
kidney cell line; RH and 90-109 are lymphoblastoid cell lines derived
Blood, Vol 87, No 5 (March 1). 1996: pp 1923-1927
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1996 by The American Society of Hematology.
OOO6-497ID6/8705-0047$3.00/0
1923
From www.bloodjournal.org by guest on January 21, 2015. For personal use only.
MADANI ET AL
1924
was verified, and Escherichia coli JM109 cells containing the recombinant plasmid were grown in Superbroth medium.'" After a 4-hour
induction by IPTG (0.1 mmolk), the GST-p13"rrP' fusion protein
was extracted and purified by Glutathione-agarose chromatography
as described." New Zealand white female rabbits were immunized
with the purified GST-pl 3Mrrp' emulsified with Freund's adjuvant.
After three boosts, the antiserum was used without further purification. Obtention of the anti-p8Mrc"' antiserum was previously reported. ''
Western blotting. Cell proteins were extracted with the Triple
Detergent Lysis Buffer,"' quantified using the BCA kit (Pierce,
Rockford, IL), size fractionated on 10% Tris-tricine sodium dodecyl
sulfate-polyacrylamide gels (SDS-PAGE)," and electrotransferred
on nitrocellulose. The membrane was blocked overnight in 10%
nonfat dry milk in PBST (phosphate-buffered saline; Tween 20,
0.1%). The antiserum was diluted 1:1,000 in blocking buffer and
applied to the membrane. After I hour of incubation, the membrane
was washed with PBST and incubated with goat-antirabbit IgGperoxidase conjugate (Boehringer Mannheim, France) for I hour.
After three washes in PBST, the membrane was overlayed with the
chemiluminescent substrate solution and developed according to the
manufacturer's instructions (ECL. Amersham, Arlington Heights,
IL).
Transient transfections. The orfl07 sequence was cloned in the
BamHl site of the eukaryote expression vector pSGS (Stratagene,
La Jolla, CA). The recombinant plasmid was transfected into the
cos-7 cell line by the calcium-phosphate method.'" Cells were trypsinized after 36 hours and analyzed by Westem blotting after protein
extraction.
DNA ana/ysi.s. High molecular weight DNA was extracted from
leukemic samples, digested by BamHl and Snc I restriction enzymes
and the resulting fragments were separated according to size by
electrophoresis through a 0.8% agarose gel. After alkaline transfer
on N'Hybond membranes (Amersham). samples were hybridized to
"P radiolabeled probes." Probes used are schematized see Fig 2A;
probes 2.SRB and I.OXH were used on T-PLL DNAs allowing an
analysis of approximately SO kb 5' to and within the MTCP l gene:
prohe 4.5RB was also used to analyze patient Lec.
cDNA cloning and sequencing. A cDNA library from the murine
T-cell lymphoma cell line EL4 (Stratagene) was screened with a
human MTCP I cDNA probe. Positive clones were in vivo excised
according to the protocols of the manufacturer and sequenced by
the dideoxynucleotide method (Pharmacia, Uppsala, Sweden).
RESULTS
Expression analysis of the MTCP 1 prodircts. Considering that the homology between TCLl and MTCPI was restricted to the pl 3MT"" product, we analyzed the expression
of p13'7cp' in T-PLLs.
Rabbit antibodies against p13MTC"were generated and a
sensitive Western blot assay was designed. The specificity
of the antibody was controlled in transiently transfected Cos7 cells in which a strong 13-kD signal was detected. corresponding to the predicted molecular weight of the product
of B1 transcripts. No 13-kD signal was detected in 90-109
and RH cell lines derived from hemophilic patients with a
Xq28 deletion including the MTCPl gene" (Fig I).
We then analyzed normal and leukemic T-cell samples.
Normal PBLs were found negative for p13M"'P' expression
(Fig 1 ) as were phytohemagglutinin (PHA)-activated lymphocytes and normal B lymphocytes (data not shown). A
series of acute T-cell lymphoblastic leukemias (9 cases),
HTLV-I positive acute T-cell leukemidymphomas (4
cases), Sezary syndromes (4 cases) and large granular lymphocyte proliferations (4 cases) was also found negative for
p13MTcp'expression (data not shown). Two previously described T-cell proliferations with known t(X; 14) translocations (Dol and Civ)'j and a series of 10 T-PLLs obtained
from different French hematologic centers were then analyzed. Diagnosis was confirmed by reviewing blood or BM
smears using FAB criteriaz3 and medical records. A weak
but unquestionable signal of 13 kD was found in Civ and
Dol, the two patients with a known t(X; 14). Among the 10
other T-PLLs analyzed, only one patient, Lec, expressed the
p13Mr'p' protein (Fig I).
The expression of the product of type A transcripts of the
MTCPl gene, ~ 8 ~ " 'was
, also studied in these samples. Contrary to what was observed for ~ 1 3 ~ ' "expression,
'
~8~'"'
waq expressed in all patients and in normal PBLs. As previously
repOrted,ls higher expression of ~ 8 ~ ' was
" found in the proliferations of Dol and Civ with known t(X;14)s. The p8""
protein was also expressed at high levels in patient Lec and,
to a lesser extent, in patient Lep (Fig 1).
2
n
-18.4
-18.4
-143
-14.3
p*MIcp'_,
Fig 1. Expressionof pl3"
and ~ 8 in~T-PLLs.
"
Detergent lysates (30 pg/lane except for Cos-pl3: 3.5 pgllane) were subjected to Tricine
SDS-PAGE using a 10% gel. Ponceau S staining was used to verify equal loading and protein integrity. lmmunoblot analyses were performed
using an anti-p13MTcp'antiserum ltop panel) and an anti-p8MTcp'antiserum (bottom panel). Samples analyzed are: negative control cell lines
with MTCPl deletions IRH and 90-109); transfected COS-7 cells expressing p13MrCP'(Cos p13); normal PBL; an ATCP (Dol), T-PLLs (coded by
8 signals
~
are
~ indicated.
"
three letters). Molecular weights are indicated in kilodaltons IkD). The p13MrCP'and ~
From www.bloodjournal.org by guest on January 21, 2015. For personal use only.
1925
~ 1 3 ~ "IN~T-CELL
'
PROLIFERATION
R
A
B S R R
-
B
I
1.OXH
14
\ I VI1
II \
Ih b
Lec.
kb
-
cation event in patient Lec occurring between the two fragments used as probes. A karyotype obtained from a frozen
sample of Lec's leukemic cells confirmed this hypothesis by
showing the presence of a t(X: 14).
Comparisori of hitrnnrr arid mirrine MTCP 1 arid hirrnan
TCL I protein .seyiterices. A murine T-cell lymphoma cell
line cDNA library was hybridized to a human MTCPI cDNA
probe and one cross-hybridizing type B murine cDNA clone
was selected and sequenced. Comparison of murine and human sequences of the open reading frame coding for
p13"""" showed a very high level of conservation at the
nucleotidic level (92%- of identity, data not shown) and at
the deduced amino-acid level (95% of identity) (Fig 3). Comparison of p l 3"'"'c"' sequences with the ~14""' sequence
showed a much lower degree of homology (p13'''cp' I'
~14""'. 39% of identity) (Fig 3).
S
R
4.5Rll
GL
kb
16,
BRRBR
- -
2.5RR
Lec.
XE
-
14-
12
GL
,
DISCUSSION
Probe :
1.OXH
Based on the results of our Western blot assay, the analysis
of the p13""'"' protein in normal and malignant T cells
showed a restricted expression in T-cell proliferations with
t(X: 14). The p13wrc"' protein was not expressed in resting
or activated normal lymphocytes and in other leukemic samples. This protein is homologous to the TCLI gene product.
P14rc'.' , which is expressed in T-cell proliferations with
I4q32. I trans location^.'^^'^^^' The specific expression of
p13""'"'
in proliferations with t(X: 14) and its homology
with ~14""' also involved in T-PLLs or related T-cell proliferations strongly suggest a role of p13MTc'" in leukemogenesis.
The 1 3MTu//p14r<'/./protein family shares no homology
with other oncoproteins. and biochemical and cellular analyses in transfected cells and in transgenic animals will be
necessary to determine in which oncogenic mechanism they
are involved. However, because p 14"'"' expression is restricted in the T-cell lineage to immature thymocytes and
activated peripheral lymphocytes, we can hypothesize that
the I 3M?"/'/lp 14""' overexpression may interfere with Tcell activation and/or differentiation. It can also be drawn
from studies in ataxia telangiectasia patients that TCLI and
MTCPl gene rearrangements occur at an early stage of leukemogenesis and are not per se sufficient for the development of malignancy,'."." hypothesis conforted by the demonstration in preleukemic T-cell proliferations of the
overexpression of p l 3"""" (this report) or p14"".'4
Chromosomal translocations involving the Xq28 region
have been so far rarely reported in malignancy.'5 Taking
advantage of our initial characterization of a t(X;14)I3 in
4.5RB
BamHI
Fig 2. Southern blot analysis of the MTCPl locus. (A) Schematic
representation of the MTCPT locus. (HIindicate the MTCPl exons.
Restriction enzymes: R, €COR/;B, BamHI; S, Sac I; X, Xho I; H, Hindlll
(only relevant Xho I and Hindlll sites are indicated). Fragments used
as probes are indicated. (B) Southern blot analysis of patient Lec.
Probes and restriction digests are indicated. Molecular weights are
indicated in kilobases (kb). Dashes indicate the germline fragments,
arrows the rearranged fragments.
Southern blot nnalvsis qf the MTCP I locirs. The MTCPl
gene was studied by standard Southern blot techniques using
two probes and two restriction digests, allowing the analysis
of approximately 50 kb 5' to and within MTCPI. T-PLL
DNAs were found in germline configuration for the MTCPl
locus with the exception of the previously reported Dol and
Civ rearrangements and of the Lec rearrangement. A germline 14-kb fragment and an abnormal 16-kb fragment were
observed using the I.OXH probe in patient Lec's BamHI
digested DNA (Fig 2B). The same blot was then probed
using the 4.5RB probe, located 3' to MTCPI exon 1 and
hybridizing to the same germline 14 kb BarnHl fragment
(see Fig 2A for schematic representation of the MTCPl locus
and localization of the probes used). An abnormal 12 kb
fragment was found in patient Lec's BarnHI digested DNA.
The Southern blot data were thus compatible with a translo-
Fig 3. Sequence comparison of human and murine p13M'CP' and human ~ 1 4 " ~ ' Sequence
.
alignment between human p13''CP' and human ~ 1 4 " ~
is'
shown according to Fu et al." Vertical bars indicate
identical amino acids. The murine p13M'CP' aminoacid sequence was deduced from the murine type B
cDNA sequence (not shown) reported to GenBank
under the accession number M U U32332.
MAREDVGAPPDELWVBQEGDEYQRTWVAV-VEEETSF-LKARVQQVWPLGD
53
II IIIIIIIIIIIIIIII IIIIIIIIIIII IIIIIII I IIIII IIIIII
MAGEDVGAPPDELWVEQEGIYDEYQRTWVAV-VEEETSF-LRARVCQIQWLGD
I l l IIII
I I I ~ I I
II
I II
53
EUp14rct'
MAECPTLGEAVTDEPDRLWAWEKWYLDEKQEAWLPLTIEIKDRLQLRV'LLRREDVVL~60
Mup13"ncP1
A T K P S E L L T S Q L P L M W Q L Y P ~ R Y M D ~ S ~ W Q I Q B E L ~ ~ Q E ~ P D 107
D
.-
Eu013-~
EuplQrL1
I
III IIIIIIIIIII IIII I IIIIIIII III IIIII IIIIIIII II I IIIII
A A R P S E L L T S O L P L M W O L Y P E E R Y M D ~ S ~ W Q I Q E E L ~ ~ O E ~ L L P D D 107
I
1-11 IlilII II
I I-- I
11- II IIIII
114
PMTPTQIGPSLLPIMWQLYPDGRYSSDSSFWP.LWEIKIDGVEDMLLELLPDD
From www.bloodjournal.org by guest on January 21, 2015. For personal use only.
1926
MADANI ET AL
the ataxia telangiectasia clonal T-cell proliferation ‘‘Dol’ ’
selected for its chromosomal aberration,‘ we have screened
for MTCPI rearrangement a series of 11 T-PLLs collected
without knowledge of the cytogenetic data. This approach
allowed us to detect two additional t(X; 14) in the T-PLLs
“Civ”” and “Lec” (this report). Considering the way we
have recruited T-PLLs in our series, a bias in selecting proliferations with t(X; 14) is unlikely. The rarity of reported
t(X; 14) cases in the literature’.’ probably reflects the rarity
of the T-cell prolymphocytic type of leukemia. The t(X; 14)
translocation, occurring in a significant proportion of T-PLLs
and related proliferations, should be considered as a marker
of these diseases.
Initial hypotheses on the role of MTCPI in leukemogenesis were misled by the fact, so far unprecedented for a mammalian gene, that this gene codes for two differents proteins.
Northern blot analyses from us and others’?-’‘ previously
detected only significant levels of type A MTCPl transcripts
in proliferations with t(X; 14). The MTCPI product coded
by these transcripts, the mitochondrial protein p8MTCP’,
was
found overexpressed in these proliferations. Is The possible
relevance in oncogenesis of p13”’C“’ was thus initially underestimated because type B 1 transcripts have been undetected in proliferations with t(X; 14) by Northem blot assay
using total RNAs, but nevertheless were coding for low but
detectable levels of p13MTCp’.
An alternative splicing mechanism contributes to generate
the different coding capab es of MTCPl transcripts.I3 The
invertly related levels of p13M7CP’and p8M7r“’ proteins in
our small series of proliferations with t(X; 14) are compatible
with a splicing regulation but could also be related to the
localization of the different Xq28 breakpoints. The mechanism by which a high expression of p8M‘Cp’ exists in some
T-PLLs without t(X; 14), especially in the T-PLL “Lep,”
when compared to normal lymphocytes (Fig 1) has also to
be clarified. Data on transcriptional and posttranscriptional
regulations of MTCPl are clearly needed to answer these
questions.
Because the mitochondrial protein p8M““ is overexpressed in T-cell proliferations with t(X; 14) and because its
biologic function is still unknown, we cannot rule out its
participation in oncogenesis. However, the specific expression of p13M‘cp’ in proliferations with t(X; 14) and the homology of this protein with ~ 1 4 “ ~represent
’
strong evidences for a key role of the p13MTCp‘/p14‘CL’protein family
in the pathogenesis of T-PLL and related diseases. Moreover,
the biologic importance of p13MTCP’
is reflected by its high
degree of conservation in mammals.
ACKNOWLEDGMENT
We thank H. de ThC and J. HBbert for comments on the manuscript, L. Grollet for oligonucleotide synthesis, A. Metzenberg and
D.P. Lillicrap for providing the RH and 90-109 cell lines, B. Boursin
for photography, and S. Labaume for help in cellular techniques.
We also thank G . Flandrin and H. Dombret for their help and support.
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3 IN~T-CELL
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~ '
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From www.bloodjournal.org by guest on January 21, 2015. For personal use only.
1996 87: 1923-1927
Expression of p13MTCP1 is restricted to mature T-cell proliferations
with t(X;14) translocations
A Madani, V Choukroun, J Soulier, V Cacheux, JF Claisse, F Valensi, S Daliphard, B Cazin, V
Levy, V Leblond, MT Daniel, F Sigaux and MH Stern
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