|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 368-373
Transgenic Mice for MTCP1 Develop T-Cell Prolymphocytic
Leukemia
By
Catherine Gritti,
Hélène Dastot,
Jean Soulier,
Anne Janin,
Marie-Thérèse Daniel,
Ali Madani,
Gisèle Grimber,
Pascale Briand,
François Sigaux, and
Marc-Henri Stern
From INSERM U462 and Laboratoire Universitaire EA2378, Institut
Universitaire d'Hématologie, Hopital Saint Louis, Paris, France;
and INSERM U380, ICGM, Paris, France.
 |
ABSTRACT |
T-cell prolymphocytic leukemia (T-PLL) is a rare form of mature
T-cell leukemia associated with chromosomal rearrangements implicating
MTCP1 or TCL1 genes. These genes encode two homologous proteins, p13MTCP1 and p14TCL1,
which share no similarity with other known protein. To determine the
oncogenic role of MTCP1, mice transgenic for MTCP1
under the control of CD2 regulatory regions (CD2-p13 mice) were
generated. No abnormality was detected during the first year after
birth. A late effect of the transgene was searched for in a cohort of 48 CD2-p13 mice aged 15 to 20 months, issued from 3 independent founders. Lymphoid hemopathies, occurring in the three transgenic lines, were characterized by lymphoid cells with an irregular nucleus,
a unique and prominent nucleolus, condensed chromatin, a basophilic
cytoplasm devoid of granules, and an immunophenotype of mature T cells.
The molecular characterization of Tcrb rearrangements demonstrated the monoclonal origin of these populations.
Histopathological analysis of the cohort demonstrated early splenic and
hepatic infiltrations, whereas lymphocytosis and medullar infiltrations were found infrequently. The engraftment of these proliferations in
H2-matched animals demonstrated their malignant nature. Cumulative incidence of the disease at 20 months was 100%, 50%, and 21% in F3,
F4, and F7 lines, respectively, and null in the control group. The
level of expression of the transgene, as estimated by Western blotting
in the transgenic lines correlated with the tumoral incidence, with the
highest expression of p13MTCP1 being found in F3
mice. CD2-p13 transgenic mice developed an hemopathy similar to human
T-PLL. These data demonstrate that p13MTCP1 is an
oncoprotein and that CD2-p13 transgenic mice represent the first animal
model for mature T-PLL.
| |
INTRODUCTION |
T-CELL PROLYMPHOCYTIC leukemia (T-PLL) is
a rare form of leukemia occurring in elderly people. It is
characterized by an aggressive tumoral syndrome, associated with
lymphocytosis, lymphadenopathy, hepatosplenomegaly, and skin lesions.
Prolymphocytes are larger than lymphocytes and have a high
nucleocytoplasmic ratio, a basophilic cytoplasm devoid of granules,
moderately condensed chromatin, and a single prominent nucleolus. The
immunophenotype is that of mature or premature T
lymphocytes.1 Similar cells have been observed in some
patients suffering from the genetic disease ataxia telangiectasia (AT).
In these AT patients, the clonal lymphoid population (named ataxia
telangiectasia clonal proliferation [ATCP]) is quiescent, but can
transform in authentic T-PLL after several years.2 These
observations suggest that ATCP is a preleukemic stage of
T-PLL.3 Recurrent chromosomal aberrations associated with
T-PLL and ATCP involve the 14q11 region, containing the TCRA/D gene, and the Xq28 or 14q32.1 regions.1 Their molecular
characterization led to the identification of the MTCP1 and
TCL1 genes, respectively.4-6 Breakpoints of the
seven t(X;14) translocations characterized at a molecular level are
5 to or within the MTCP1 gene.4,5,7-9 This
gene is organized into seven exons spread over approximately 10 kb.
Alternative splicing generates A and B transcripts encoding two
entirely different proteins, p8MTCP1 and
p13MTCP1, an arrangement that is highly unusual in
vertebrates.4 B transcripts contain the 7 exons of the gene
and encode p13MTCP1, a 13-kD protein whose
expression has only been detected so far in t(X;14)-associated T-cell
proliferations.8,10 This protein shares significant
homology with the product of TCL1,
p14TCL1.11 Elucidation of the
three-dimensional structure has confirmed that
p13MTCP1 and p14TCL1 have a
similar structure shared by no other known protein.12,13 These indirect evidences suggest that p13MTCP1 is
the oncogenic product of MTCP1. However,
p13MTCP1 and p14TCL1 do not
resemble other known oncoproteins, no functional role has been so far
attributed to them, and in vitro transformation assays remained
negative (unpublished data). The possibility that MTCP1 is oncogenic was thus investigated by generating
transgenic mice overexpressing p13MTCP1 in T cells.
No phenotypic abnormality was observed before the age of 15 months,
when clinically or biologically detectable hemopathies similar to human
T-PLL started to appear. We present here the analysis of this
transgenic cohort.
| |
MATERIALS AND METHODS |
CD2-p13 transgenic mice.
The CD2-p13 transgenic construct, was made by cloning in the
EcoRI site of the CD2 vector,14 a fragment
corresponding to the open reading frame of human MTCP1 coding
for p13MTCP1, which shares 95% of identity with
the murine p13MTCP1 protein.8
Transgenic mice were generated using a Sal I-Xba I
fragment encompassing the insert. Three founders were obtained (F3, F4,
and F7) and bred. Transgenic heterozygote mice issued from these
founders were studied and compared with nontransgenic siblings raised
in identical conditions. Tumoral analysis was conducted on 77 mice aged
from 15 to 20 months, including 48 transgenics (12 F3, 22 F4, and 14 F7) and 29 nontransgenic siblings.
Genotyping the mice.
Genotyping was performed on tail DNAs using the Nucleospin C&T kit
(Macherey-Nagel, Hoerdt, France). Polymerase chain reaction (PCR) was
performed on 5 µL DNA in a final mix containing 200 ng of CD2 primer
(5-GTGTGGACTCCACCAGTC-3), 200 ng of III/IV primer
(5-CCCCTGACCATTAAA-3), 0.2 mmol/L deoxyribonucleotides, 1× Taq buffer (Boehringer, Meylan, France), and 0.5 µL Taq
polymerase (Boehringer). A 30-cycle amplification was performed
(94°C for 15 seconds, 44°C for 15 seconds, and 72°C for 15 seconds) after an initial denaturation step of 3 minutes at 94°C. A
specific band of 400 bp was shown on a 1.5% agarose gel. A final check of the transgenic status was performed by Southern blot on high molecular weight DNA extracted from splenic cells using the QIAamp Blood kit (Qiagen, Hilden, Germany). DNAs were digested by
BamHI restriction enzyme 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, Les Ulis, France), samples were hybridized to 32P-radiolabeled CD2
minigene 2-kb BamHI fragment and shown by autoradiography. A
2-kb band showed the transgenic status of the mice.
Western blotting.
Cell proteins were extracted with the Triple Detergent Lysis
Buffer,15 quantified using the BCA kit (Pierce, Rockford,
IL), sized-fractionated on 15% Tris-glycine sodium dodecyl
sulfate-polyacrylamide gels (SDS-PAGE), and electrotransferred onto
nitrocellulose. The membrane was blocked overnight in 10% nonfat dried
milk in PBST (phosphate-buffered saline [PBS]: 7.6 g/L NaCl, 0.7 g/L
Na2PO4, 0.2 g/L KPO4, and 0.1%
Tween 20). The previously described antiserum anti-p13MTCP1 was diluted 1:1,000 in the blocking
buffer and applied to the membrane.8 After 1 hour of
incubation, the membranes were washed with PBST and incubated with goat
antirabbit IgG-peroxidase conjugate (Boehringer) for 1 hour. After
three washes in PBST, the membranes were overlaid with the
chemiluminescent substrate solution and developed according to the
manufacturer's instructions (ECL; Amersham). The same membrane was
then probed using a monoclonal antibody against actin (AB-1; Oncogene
Science, Paris, France) and a sheep antimouse peroxidase conjugate
(Amersham) to control loading.
White blood cell (WBC) count.
Blood was collected from the cavernous sinus with a capillary tube in a
tube coated with EDTA (Microtainer Brand; Becton Dickinson, Orders,
France). Smears were immediately prepared and stained with May
Grünwald Giemsa. Full counts were made on a cell counter (Coulter
STKS; Coultronics, Margency, France).
Fluorescence-activated cell sorting (FACS) analysis of
the splenic cells.
Spleens were weighed and dissociated in 10 mL RPMI 1640 (GIBCO BRL,
Life Technologies, Cergy Pontoise, France) between two frosted slides.
Cell suspensions were spun for 5 minutes at 1,500 rpm, the red blood
cells were then lyzed in ACK (0.15 mol/L NH4Cl, 1 mmol/L
KHCO3, 0.1 mmol/L EDTA), spun for 5 minutes at 1,500 rpm,
and twice washed in 0.9% NaCl. Cells were counted and resuspended in
PBS at 107 cells/mL. Immunophenotyping was performed with
monoclonal antibodies anti-CD3, CD4, CD8, CD25, and B220 (PharMingen,
San Diego, CA), directly coupled to fluorescein isothiocyanate (FITC;
CD3, CD8) or to phycoerythrin (PE; CD8, CD25, B220). A 50-µL sample
of cell suspension was incubated for 30 minutes at +4°C with 1 µL
antibody at the appropriate dilution and washed in 2 mL of PBS-0.2%
sodium azide. Cells were resuspended in 700 µL of the same buffer and analyzed on a fluorescent cell sorter (FACS Scan; Becton Dickinson).
Cell sorting.
Splenic cells of a 5-month-old F3 mouse were stained with monoclonal
antibodies against CD4, CD8, CD3, or B220. Positive fractions were
sorted on a FACS Scan cell sorter. The purity of the fractions was
evaluated by analysis on a FACS Scan cytometer and was greater than
95% in all cases.
Analysis of the Tcrb gene configuration by Southern blot.
Tcrb rearrangements were analyzed by Southern blotting on
HindIII-digested splenocyte DNAs. A serial dilution of tumoral
DNA in normal splenic DNA (100%, 25%, and 10%) was included on each blot to quantify the intensity of clonal rearrangements. Clonal rearrangements accounting for less than 10% of the splenocytes were
considered as not significant. The probes used were the 650-bp EcoRI fragment of 86T5 cDNA,16 which hybridizes to
murine Tcrb C 1 and C2 regions,
and the 286-bp Pst I-Cla I fragment containing the
J2.6 segment of the murine Tcrb.
Histopathology.
Organs were fixed in AFA (80% ethanol, 15% formaldehyde, 5% acetic
acid) for 2 to 4 hours and further processed for paraffin embedding.
Three-micrometer sections were stained with
hematoxylin-eosin and analyzed by two different pathologists.
Transplantation of leukemic cells.
Ten million leukemic cells resuspended in PBS were intravenously
injected in 4- to 6-week-old C57BL/6 × DBA/2 mice. Neither speed
nor efficiency of engraftment was enhanced in 2.5 Gy irradiated animals.
| |
RESULTS AND DISCUSSION |
Characterization of CD2-p13 transgenic mice.
We generated transgenic mice in which expression of
p13MTCP1 was controlled by the CD2 regulatory
sequences (CD2-p13 mice).14 Three transgenic mice (F3, F4,
and F7) were obtained and bred. The expression of the transgene was
evaluated on each lineage by Western blot on proteins extracted from
thymus, spleen, and nonlymphoid organs. The three transgenic lines
expressed p13MTCP1 in thymuses at different levels:
high for F3, intermediate for F4, and weak for F7
(Fig 1A). Expression was weaker in spleens, but the gradation between the lineages was maintained. No expression was detected in the nonlymphoid organs (data not shown). The transgene expression was then analyzed in lymphoid subpopulations. The
p13MTCP1 protein was detected in CD4+
and CD8+ splenocytes at comparable levels, but not in B
lymphocytes (Fig 1B). No difference in the size or distribution of the
T-cell subpopulations was detected in a series of transgenic mice aged
from 6 weeks to 1 year compared with nontransgenic siblings (data not
shown).
View larger version (37K):
[in this window]
[in a new window]
| Fig 1.
Transgene expression in CD2-p13 mice. Detergent lysates
were subjected to SDS-PAGE through a 15% gel. Immunoblot analysis was
performed using the anti-p13 rabbit antiserum (upper panel) and loading
was estimated using anti-actin monoclonal antibody (lower panel). (A)
Expression analysis in the three transgenic lines. Thymocytes (Thymus)
and splenocytes (Spleen) were analyzed in transgenics (F3, F4, and F7)
and nontransgenic control mouse (C). (B) Expression analysis in the
lymphoid subpopulations. CD3+ cells (CD3),
CD4+ cells (CD4), CD8+ cells (CD8), and
B220+ B cells (B) from a F3 transgenic mouse spleen were
purified by cell sorting (purity >95%) and compared with total
splenocytes of this mouse (total). Arrows indicate the p13-and
actin-specific signals.
|
|
Elderly CD2-p13 transgenic mice develop T-PLL.
The prolonged survey of the animal cohort resulted in the detection of
mice suffering from leukemic syndromes. Seven mice from the cohort aged
from 15 to 18 months died of various causes (2 urogenital tumors and 1 polyclonal lymphadenitis in transgenic and control animals) and of 4 cases of leukemia in F4 transgenics. Because of the short delay between
the clinically detectable stage of the disease and the distress of the
animals, the remainder of the cohort (44 transgenics) was killed at 18 to 20 months of age, as well as 29 nontransgenic age-matched siblings,
and studied.
Cytological examination of blood smears and spleen appositions in
transgenic mice showed frequent invasion of lymphoid cells characterized by an irregular nucleus with condensed chromatin containing a unique and prominent nucleolus and by a basophilic cytoplasm devoid of granules (Fig 2B).
Histopathological examination demonstrated constant infiltrations of
spleens and livers by these abnormal lymphoid cells in presence or
absence of organomegaly (Fig 2A, C, D, and E). The immunophenotype of
the leukemic cells, when tested, was
CD3+CD8+CD4 CD25B220
in 23 cases, and was
CD3+CD4+CD8CD25B220
in 1 case (Fig 3). The rarity of
CD4+ T-cell leukemia was not due to a lower level of
expression of p13MTCP1 in the CD4+
subset (Fig 1B). In humans, MTCP1 aberrations are associated with CD4+CD8+,
CD4CD8+, and
CD4+CD8 T-PLLs.1 Subtle
differences in T-cell differentiation and physiology in the two species
may thus account for the preferential transformation of
CD8+ cells in the transgenics. In all but 3 cases, these
cells were larger than normal peripheral blood lymphocytes based on the
forward scatter (FSC) histogram in FACS analysis (Fig 3B and C). The
three normally sized clonal populations were reminiscent of the small cell variant of the human T-PLL, alternatively named T-cell chronic lymphocytic leukemia (Fig 3D).1,17 Clonality of T-cell
proliferations was demonstrated by Southern blot analysis of Tcrb
gene rearrangements (Fig 4). This
leukemic disease fitted all criteria defining the human
T-PLL.18
View larger version (76K):
[in this window]
[in a new window]
| Fig 2.
Histopathological analysis of the CD2-p13 mice. (A)
Macroscopic view of a F4 CD2-p13 transgenic mouse showing an enlarged spleen of 1,100 mg. (B) Photomicrography of a typical T-cell
prolymphocyte from a F4 CD2-p13 transgenic mouse. The blood smear was
stained with May-Grünwaltd-Giemsa. (C through E) Histology of
spleen (C) and liver (D and E) after hematoxylin-eosin staining. (C) The spleen has lost its normal architecture and is infiltrated by
prolymphocytes beyond its capsule. (D) Low magnification of the liver
showing large amounts of prolymphocytes surrounding portal tracts. (E)
High magnification of the liver showing numerous prolymphocytes within
sinusoids.
|
|
View larger version (25K):
[in this window]
[in a new window]
| Fig 3.
FACS analysis of splenic populations. (Upper panel) FSC
histogram analyzing the cell size. A rectangle defines the normal sized
splenocytes. (Lower panel) CD4 and CD8 double fluorescence patterns.
(A) Analysis of normal control splenocytes. (B) Analysis of a
transgenic mouse with a major tumoral load. Nearly all splenic cells
are large sized CD8+ prolymphocytes. (C) Analysis of a
transgenic mouse with minor tumoral load. FCS histogram shows a larger
than normal sized cell population with a CD8+ phenotype
(not shown). (D) Analysis of a small cell variant. An excess of
CD8+ cells is clearly visible, but no larger than normal
cells are detected on the FSC histogram.
|
|
View larger version (58K):
[in this window]
[in a new window]
| Fig 4.
Analysis of Tcrb rearrangements. (Upper panel) A
schematic representation of the murine Tcrb gene is shown with
its V, D, J, and C segments. The relevant HindIII
sites (H) are shown. The J 2 and C probes are shown as
thick lines. (Lower panel) An example of Southern blot analysis is
shown. Mouse splenic DNAs are analyzed on lanes 1 through 18. Quantification of the clonal rearrangements is made by comparison to a
serial dilution of tumoral DNA into normal spleen DNA (100%, 25%, and
10%) included on each membrane. Black arrows indicate the clonal
Tcrb rearrangements. The open arrow shows incomplete DJ
rearrangements that were not taken into account. Samples in lanes 9, 10, and 17 demonstrated major tumor loads. Samples in lanes 2 and 15 demonstrated minor tumoral loads.
|
|
Invasion staging and incidence of the disease.
The analysis of the transgenic mice given above defined two stages of
the disease. Major tumoral load was defined by clonal T-cell
rearrangements in more than 25% of the splenocytes (Fig 4) and more
than 60% of monomorphic CD3+CD8+ or
CD3+CD4+ splenocytes in FACS analysis (Fig 3B).
This had occurred in 10 cases (Table 1). In
these cases, lymphocytosis and splenomegaly were frequent but not
constant (mean WBC, 226 × 109 cells/L; range, 13 to
1,470 × 109 cells/L; mean spleen weight, 909 mg;
range, 87 to 2,700 mg). Major tumoral load (splenomegaly of 30 times
the normal weight [as shown on Fig 2A] and lymphocytosis as high as
2,000 × 109 cells/L) was occasionally associated with
near normal behavior of the animals. A complete histological analysis
of 3 florid cases showed an infiltration of all lymphoid organs,
livers, and lungs. Infiltration of other organs was not constant: bone
marrow was invaded in only 1 case and testes were normal in all cases.
Tumor cells from these 10 major T-cell clonal hemopathies were
intravenously injected into H2-compatible immunocompetent mice. In 9 cases, the tumors engrafted and lymphocytosis was detectable in 1 to 4 months, demonstrating the malignant nature of these proliferations.
In 16 cases, the presence of a clonal T-cell population in the spleen
was only detected by the Southern blot analysis (Fig 4) and was not
linked to organomegaly or lymphocytosis. Intensity of these clonal
rearrangements correlated with the extent of the invasion evaluated by
FACS analysis and histological studies, except in one tumor in which
the proportion of CD8+ large cells exceeded the intensity
of the Tcrb clonal rearrangement, suggesting in this case the
presence of a polyclonal prolympho-cytic cell population.
Prolymphocytic infiltration of the liver was constantly demonstrated in
these 16 cases by histological analyses. In all but 3 cases, clonal
rearrangements were associated with the presence of larger than normal
CD8+ T cells (Fig 3C). The cases of small cell variant
occurred in F4 (1 case) and F7 (2 cases) lines.
Altogether, a T-cell hemopathy was detected in all 12 transgenic mice
(100%) issued from founder F3, 11 of 22 transgenics (50 %) issued
from founder F4, 3 of 14 transgenics (21%) issued from founder F7, and
none of the 29 sibling controls (Table 1). The incidence of the disease
correlated with the level of expression of
p13MTCP1 in the transgenic lines (Fig 1A),
suggesting a dose-response effect of p13MTCP1.
However, other genetic factors are probably involved, because hemopathies appeared earlier and were more severe in the F4 transgenic line, whereas the incidence was higher in the F3 line.
MTCP1 is an oncogene.
The presence of T-cell leukemia in the three transgenic lines and in
none of the nontransgenic siblings clearly demonstrated that
MTCP1 is an oncogene coding for a 13-kD oncoprotein.
Conversely, no in vitro or in vivo transformation assays demonstrated
any oncogenic activity for the alternative and more abundant product of
MTCP1, an ubiquitous 8-kD mitochondrial protein (Stern et al, unpublished data). The products of the MTCP1 and
TCL1 genes, p13MTCP1 and
p14TCL1, now constitute a new oncogene family of
yet unknown biological function.
T-PLL in CD2-p13 transgenic mice.
The murine hemopathy arising in CD2-p13 transgenics is, to our
knowledge, previously undescribed in mice and shares most of the
clinical and biological features of the human T-PLL. Its late onset
(after 15 months) in transgenics also mimics the human T-PLL that
arises generally in the elderly. The only noticeable differences are
that human T-cell prolymphocytic cells have a more diverse immunophenotype and frequently infiltrate the skin when compared with
the CD2-p13 mice. The natural history of the human T-PLL was inferred
from patients with AT. These studies showed that the emergence of
clonal T-cell population with all the biological characteristics of
T-cell prolymphocytes precede lymphocytosis by many
years.2,3 The hemopathy observed in CD2-p13 transgenics fits this model. Furthermore, the early and latent hepatosplenic prolymphocytic invasion in transgenics, which precedes the leukemic syndrome, suggests a similar preclinical stage for the human disease. The latency period before emergence of the tumors, which is longer than
in most murine models of oncogenesis, is in agreement with the
necessity of several genetic events in addition to the activation of
MTCP1 (or TCL1) in the development of the T-PLL. To
date, studies of the human disease have demonstrated the importance of
the inactivation of the ATM gene19-21 and of the
duplication of the long arm of chromosome 8.1,22 The
striking similarity of the human and murine T-PLLs makes CD2-p13 mice a
valuable model to investigate the biological functions of the family of
oncoproteins formed by p13MTCP1 and
p14TCL1, to identify the secondary events necessary
for the malignant phenotype, and to test therapeutics.
| |
NOTE ADDED IN PROOF |
Interestingly, transgenic mice with TCL1, a gene with high
similarity to MTCP1, under the control of the 1ck promoter
developed similar mature CD8+ T-cell leukemias (Virgilio et
al, Proc Natl Acad Sci USA 95:3885, 1998).
| |
FOOTNOTES |
Submitted March 11, 1998;
accepted April 21, 1998.
Supported by l'INSERM and la Ligue Nationale Contre le Cancer.
Address reprint requests to Marc-Henri Stern, MD, PhD, Unité
INSERM U462, Centre Hayem, Hopital Saint Louis, 75475 Paris Cedex 10, France; e-mail: mh.stern{at}chu-stlouis.fr.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank P. Blanchet, M. Chopin, and M. Pla for their help in
generating and raising the transgenic animals; D. Kioussis for the gift
of the CD2 minigene construct; C. Guyonnet for reviewing liver
sections; M. Schmid for cell sorting; C. Green for critical reading;
and J. Boisse and R. Nancel for artwork.
| |
REFERENCES |
1.
Matutes E,
Brito-Bapapulle V,
Swansbury J,
Ellis J,
Morilla R,
Dearden C,
Sempere A,
Catovsky D:
Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia.
Blood
78:3269,
1991[Abstract/Free Full Text]
2.
Taylor AMR,
Metcalfe JA,
Thick J,
Mak YF:
Leukemia and lymphoma in ataxia telangiectasia.
Blood
87:423,
1996[Abstract/Free Full Text]
3.
Stern MH,
Theodorou I,
Aurias A,
Maier-Redelsperger M,
Debre M,
Debre P,
Griscelli C:
T-cell nonmalignant clonal proliferation in ataxia telangiectasia: A cytological, immunological, and molecular characterization.
Blood
73:1285,
1989[Abstract/Free Full Text]
4.
Stern MH,
Soulier J,
Rosenzwajg M,
Nakahara K,
Canki-Klain N,
Aurias A,
Sigaux F,
Kirsch IR:
MTCP-1: A novel gene on the human chromosome Xq28 translocated to the T cell receptor alpha/delta locus in mature T cell proliferations.
Oncogene
8:2475,
1993[Medline]
[Order article via Infotrieve]
5.
Fisch P,
Forster A,
Sherrington PD,
Dyer MJ,
Rabbitts TH:
The chromosomal translocation t(X;14)(q28;q11) in T-cell pro-lymphocytic leukaemia breaks within one gene and activates another.
Oncogene
8:3271,
1993[Medline]
[Order article via Infotrieve]
6.
Virgilio L,
Narducci MG,
Isobe M,
Billips LG,
Cooper MD,
Croce CM,
Russo G:
Identification of the TCL1 gene involved in T-cell malignancies.
Proc Natl Acad Sci USA
91:12530,
1994[Abstract/Free Full Text]
7.
Thick J,
Mak Y-F,
Metcalfe J,
Beatty D,
Taylor AMR:
A gene on chromosome Xq28 associated with T-cell prolymphocytic leukemia in two patients with ataxia telangiectasia.
Leukemia
8:564,
1994[Medline]
[Order article via Infotrieve]
8.
Madani A,
Choukroun V,
Soulier J,
Cacheux V,
Claisse JF,
Valensi F,
Daliphard S,
Cazin B,
Levy V,
Leblond V,
Daniel MT,
Sigaux F,
Stern MH:
Expression of p13MTCP1 is restricted to T-cell proliferations with t(X;14) translocations.
Blood
87:1923,
1996[Abstract/Free Full Text]
9.
Gritti C,
Choukroun V,
Soulier J,
Madani A,
Dastot H,
Leblond V,
Radford-Weiss I,
Valensi F,
Varet B,
Sigaux F,
Stern M:
Alternative promotor of p13MTCP1-encoding transcripts in mature T-cell proliferations with t(X;14) translocations.
Oncogene
15:1329,
1997[Medline]
[Order article via Infotrieve]
10.
Thick J,
Metcalfe JA,
Mak YF,
Beatty D,
Minegishi M,
Dyer MJ,
Lucas G,
Taylor AMR:
Expression of either the TCL1 oncogene, or transcripts from its homologue MTCP1/c6.1B, in leukaemic and non-leukaemic T cells from ataxia telangiectasia patients.
Oncogene
12:379,
1996[Medline]
[Order article via Infotrieve]
11.
Fu TB,
Virgilio L,
Narducci MG,
Facchiano A,
Russo G,
Croce CM:
Characterization and localization of the TCL-1 oncogene product.
Cancer Res
54:6297,
1994[Abstract/Free Full Text]
12.
Yang YS,
Guignard L,
Padilla A,
Hoh F,
Strub MP,
Stern MH,
Lhoste JM,
Roumestand C:
Solution structure of the recombinant human oncoprotein p13MTCP1.
J Biomol NMR
11:339,
1998
13.
Hoh F,
Yang YS,
Guignard L,
Padilla A,
Stern MH,
Lhoste JM,
van Tilbeurgh H:
Crystal struture of p14TCL1, an oncogene product involved in T-cell prolymphocytic leukemia, reveals a novel -barrel topology.
Structure
6:147,
1998[Medline]
[Order article via Infotrieve]
14.
Robey EA,
Fowlkes BJ,
Gordon JW,
Kioussis D,
von Boehmer H,
Ramsdell F,
Axel R:
Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage.
Cell
64:99,
1991[Medline]
[Order article via Infotrieve]
15. Sambrook J, Fritsch EF, Maniatis T: Molecular Cloning: A
Laboratory Manual. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, 1989
16.
Hedrick SM,
Nielsen EA,
Kavaler J,
Cohen DI,
Davis MM:
Sequence relationships between putative T-cell receptor polypeptides and immunoglobulins.
Nature
308:153,
1984[Medline]
[Order article via Infotrieve]
17.
Hoyer JD,
Ross CW,
Li CY,
Witzig TE,
Gascoyne RD,
Dewald GW,
Hanson CA:
True T-cell chronic lymphocytic leukemia: A morphologic and immunophenotypic study of 25 cases.
Blood
86:1163,
1995[Abstract/Free Full Text]
18.
Bennett JM,
Catovsky D,
Daniel MT,
Flandrin G,
Galton DAG,
Gralnick HR,
Sultan C:
Proposals for the classification of chronic (mature) B and T lymphoid leukaemias.
J Clin Pathol
42:567,
1989[Abstract/Free Full Text]
19.
Stilgenbauer S,
Schaffner C,
Litterst A,
Liebisch P,
Gilad S,
Bar-Shira A,
James MR,
Lichter P,
Dohner H:
Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.
Nat Med
3:1155,
1997[Medline]
[Order article via Infotrieve]
20.
Stoppa-Lyonnet D,
Soulier J,
Laugé A,
Dastot H,
Garand R,
Sigaux F,
Stern M:
Inactivation of the ATM gene in T-cell prolymphocytic leukemias.
Blood
91:3920,
1998[Abstract/Free Full Text]
21.
Vorechovsky I,
Luo L,
Dyer MJ,
Catovsky D,
Amlot PL,
Yaxley JC,
Foroni L,
Hammarstrom L,
Webster AD,
Yuille MA:
Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.
Nat Genet
17:96,
1997[Medline]
[Order article via Infotrieve]
22.
Mossafa H,
Brizard A,
Huret JL,
Brizard F,
Lessard M,
Guilhot F,
Tanzer J:
Trisomy 8q due to i(8q) or der (8) t(8;8) is a frequent lesion in T-prolymphocytic leukemia: Four new cases and a review of the literature.
Br J Haematol
86:780,
1994[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
E. Le Toriellec, G. Despouy, G. Pierron, N. Gaye, M. Joiner, D. Bellanger, A. Vincent-Salomon, and M.-H. Stern
Haploinsufficiency of CDKN1B contributes to leukemogenesis in T-cell prolymphocytic leukemia
Blood,
February 15, 2008;
111(4):
2321 - 2328.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Herling, K. A. Patel, M. A. Teitell, M. Konopleva, F. Ravandi, R. Kobayashi, and D. Jones
High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia
Blood,
January 1, 2008;
111(1):
328 - 337.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Despouy, M. Joiner, E. Le Toriellec, R. Weil, and M. H. Stern
The TCL1 oncoprotein inhibits activation-induced cell death by impairing PKC{theta} and ERK pathways
Blood,
December 15, 2007;
110(13):
4406 - 4416.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Noguchi, V. Ropars, C. Roumestand, and F. Suizu
Proto-oncogene TCL1: more than just a coactivator for Akt
FASEB J,
August 1, 2007;
21(10):
2273 - 2284.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Yano, K. Imai, A. Shimizu, and T. Hanashita
A new method for gene discovery in large-scale microarray data
Nucleic Acids Res.,
March 14, 2006;
34(5):
1532 - 1539.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-M. Kang, M. G. Narducci, C. Lazzeri, A. M. Mongiovi, E. Caprini, A. Bresin, F. Martelli, J. Rothstein, C. M. Croce, M. D. Cooper, et al.
Impaired T- and B-cell development in Tcl1-deficient mice
Blood,
February 1, 2005;
105(3):
1288 - 1294.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Auguin, P. Barthe, C. Royer, M.-H. Stern, M. Noguchi, S. T. Arold, and C. Roumestand
Structural Basis for the Co-activation of Protein Kinase B by T-cell Leukemia-1 (TCL1) Family Proto-oncoproteins
J. Biol. Chem.,
August 20, 2004;
279(34):
35890 - 35902.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. K. Hoyer, S. W. French, D. E. Turner, M. T. N. Nguyen, M. Renard, C. S. Malone, S. Knoetig, C.-F. Qi, T. T. Su, H. Cheroutre, et al.
Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma
PNAS,
October 29, 2002;
99(22):
14392 - 14397.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. G. Narducci, M. T. Fiorenza, S.-M. Kang, A. Bevilacqua, M. Di Giacomo, D. Remotti, M. C. Picchio, V. Fidanza, M. D. Cooper, C. M. Croce, et al.
TCL1 participates in early embryonic development and is overexpressed in human seminomas
PNAS,
September 3, 2002;
99(18):
11712 - 11717.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Kunstle, J. Laine, G. Pierron, S.-i. Kagami, H. Nakajima, F. Hoh, C. Roumestand, M.-H. Stern, and M. Noguchi
Identification of Akt Association and Oligomerization Domains of the Akt Kinase Coactivator TCL1
Mol. Cell. Biol.,
March 1, 2002;
22(5):
1513 - 1525.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D Kamnasaran and D W Cox
Current status of human chromosome 14
J. Med. Genet.,
February 1, 2002;
39(2):
81 - 90.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Pekarsky, C. Hallas, and C. M. Croce
Molecular Basis of Mature T-Cell Leukemia
JAMA,
November 14, 2001;
286(18):
2308 - 2314.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Carron, F. Cormier, A. Janin, V. Lacronique, M. Giovannini, M.-T. Daniel, O. Bernard, and J. Ghysdael
TEL-JAK2 transgenic mice develop T-cell leukemia
Blood,
June 15, 2000;
95(12):
3891 - 3899.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. G. Narducci, E. Pescarmona, C. Lazzeri, S. Signoretti, A. M. Lavinia, D. Remotti, E. Scala, C. D. Baroni, A. Stoppacciaro, C. M. Croce, et al.
Regulation of TCL1 Expression in B- and T-Cell Lymphomas and Reactive Lymphoid Tissues
Cancer Res.,
April 1, 2000;
60(8):
2095 - 2100.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Teitell, M. A. Damore, G. G. Sulur, D. E. Turner, M.-H. Stern, J. W. Said, C. T. Denny, and R. Wall
TCL1 oncogene expression in AIDS-related lymphomas and lymphoid tissues
PNAS,
August 17, 1999;
96(17):
9809 - 9814.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sugimoto, T. Hatakeyama, M. G. Narducci, G. Russo, and M. Isobe
Identification of the TCL1/MTCP1-like 1 (TML1) Gene from the Region Next to the TCL1 Locus
Cancer Res.,
May 1, 1999;
59(10):
2313 - 2317.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Pekarsky, C. Hallas, M. Isobe, G. Russo, and C. M. Croce
Abnormalities at 14q32.1 in T cell malignancies involve two oncogenes
PNAS,
March 16, 1999;
96(6):
2949 - 2951.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract