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Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, IDI-IRCCS, Rome 00167, Italy [M. G. N., C. L., S. S., E. S., G. R.]; Department of Experimental Medicine and Pathology, University "La Sapienza," Rome 00161, Italy [E. P., A. M. L., C. D. B., A. S.]; Division of Pathology, Azienda Ospedaliera S. Giovanni-Addolorata, Rome 00184, Italy [D. R.]; and Kimmel Cancer Institute and Kimmel Cancer Center, Philadelphia, Pennsylvania 19107 [C. M. C.]
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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The TCL1 gene (3) and the newly cloned TCL1/MTCP1-like 1 (TCL1b) gene at human chromosome 14q32.1 (4 , 5) and their homologue, the MTCP1 gene at Xq28 (6) , are involved in the leukemogenesis of mature T cells. Indeed, overexpression of TCL1/MTCP1 genes is observed in more than 90% of T-PLLs (3 , 7, 8, 9) . This T leukemia often occurs in patients with the genetic syndrome ataxia telangiectasia and is frequently associated with mutations in the ATM gene (10) .
Transgenic animals overexpressing either activated TCL1 or MTCP1 gene develop mature T-cell leukemias, indicating that these genes are directly involved in leukemogenesis (11 , 12) . However, few data have been obtained regarding their physiological function. Recently, the crystal structures of human recombinant TCL1 and MTCP1 proteins have been determined, showing a novel ß barrel topology that resembles the structure of lipocalin and calycin proteins (13 , 14) . This structural similarity suggests that TCL1 and MTCP-1 form a unique family of proteins that is predicted to bind small hydrophobic ligands (14) . Analysis of TCL1 expression in organs, tissues, subpopulations of B and T cells of bone marrow and thymus, and a large panel of cell lines indicates that TCL1 is mainly expressed in cells of lymphoid lineage (3 , 15 , 16) . Constitutive expression observed in normal fetal B cells sorted into subpopulations from bone marrow showed that TCL1 expression begins as early as at the CD34+CD19+ pro-B-cell stage. Its expression peaks in pro-B cell CD19hi IgM-, persists in immature CD19+µlo, and decreases to a minimal level in more mature B cells (CD19+µhi; Ref. 3 ). Conversely, TCL1 expression is detectable in fetal thymocytes sorted into subpopulations in very immature CD4-CD8-CD3- thymocytes, but not in more mature CD4+CD8+ and CD4+CD8- or CD4-CD8+ cells. Moreover, the study of a variety of T-ALL cell lines for TCL1 expression indicated that it is not present in these cells (8) .
In this report, we used an immunohistochemical approach by using a recently generated MoAb against TCL1 to study its expression in reactive lymphoid tissues of lymph nodes and spleen and in 194 cases of B- and T-cell lymphomas/leukemias, spanning the whole spectrum of these neoplasms. In addition, we used this new antibody in FACS to detect TCL1 protein in normal and pathological peripheral blood, and we refined the analysis of subcellular extracts by Western blot to localize the TCL1 protein to the cytoplasm and nucleus compartment.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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for details). Pathological specimens were classified according
to the Revised European and American Lymphoma classification.
Primary cutaneous lymphomas were diagnosed according to the European
Organization for Research and Treatment of Cancer classification.
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Immunohistochemistry.
For immunohistochemical studies, paraffin-embedded sections were
heated for 1 h at 55°C. After dewaxing, the slides were
rehydrated through a graded ethanol series and distilled water,
immersed in PBS (pH 7.4), and then treated with 0.1% trypsin solution
in Tris buffer for 30 min at 37°C. Endogenous peroxidase was blocked
with 3% hydrogen peroxide, and nonspecific binding was blocked with
10% normal serum. Immunostaining was performed by incubating the
27D6/20 MoAb specific for recombinant human TCL1 protein at a
concentration of 0.01 µg/µl.
Immunohistochemical staining was performed by using alkaline phosphatase anti-alkaline phosphatase and streptoavidin-biotin peroxidase labeling methods (19 , 20) .
Cell Culture.
SUPT11 is a T-ALL cell line established from a patient with mature
T-lymphocytic leukemia carrying a t(14;14)(q11;q32.1) and
overexpressing TCL1. MOLT4 is a T-ALL cell that does not express TCL1,
and it has been used as a negative control. These cells were grown in
suspension in RPMI 1640 (Life Technologies, Inc., Gaithersburg, MD)
supplemented with 10% bovine calf serum (Life Technologies, Inc.). All
cells were maintained in a humid incubator at 5%
CO2 and 37°C.
Flow Cytometry Analysis.
For detection of intracellular TCL1 expression, FACS was performed as
described previously (21)
. PBMCs from normal donors and
from a T-PLL patient were purified by Ficoll-Hypaque
centrifugation. Because TCL1 is an intracellular antigen, mononuclear
cells were previously fixed in 4% paraformaldehyde in PBS for 10 min
at 4°C and permeabilized in 0.1% saponin in PBS for 10 min at room
temperature. The treated cells were incubated with unconjugated mouse
antihuman TCL1 antibody (27D6/20) diluted in saponin buffer at a
final concentration of 1 ng/µl for 30 min at room temperature. Cells
stained with an irrelevant mouse IgG1 MoAb (Becton Dickinson, San Jose,
CA) were used as a negative control to rule out nonspecific staining.
After this step, phycoerythrin-conjugated goat antimouse IgG
(Dakopatts, Glostrup, Denmark) diluted in saponin buffer was used to
detect TCL1 protein. Flow cytometry was performed by FACScan (Becton
Dickinson). The data were analyzed using WinMDI (Joseph Trotter,
Scripps Institute, La Jolla, CA) or Cell Quest (Becton Dickinson)
software.
Preparation of Cellular Fractions and Immunoblotting.
To determine the presence of TCL1 in both nuclear and cytoplasmic
fractions, SUPT11 and MOLT4 cells were fractionated by a modification
of the procedure described previously (22)
. Suspension
cells were harvested at 1200 rpm and washed once with PBS at 4°C (all
of the subsequent steps were performed at 4°C). Cell pellets were
lysed in a 1.5 packed cell pellet volume of 10 mM
HEPES (pH 7.9), 1.5 mM MgCl2, 10
mM KCl, 0.5 mM DTT, and 0.5 mM
phenylmethylsulfonyl fluoride on ice. The cells were collected at
1300 x g for 10 min, and the supernatant
(cytoplasmic fraction) was carefully decanted. The resultant pellet was
resuspended again as described previously in 1 pellet volume with the
same buffer and centrifuged again. This step was repeated twice more,
and the supernatants were pulled together. Contaminating organelles and
whole cells were removed by adding 0.l volume of detergent solution
(one part 10% sodium deoxycholate and two parts 10% NP40) to the last
wash. Nuclear and cytoplasmic fractions were adjusted to equivalent
volumes with Laemmli Sample Buffer. The extracts were resolved on 12%
polyacrylamide gels and electrotransferred to nitrocellulose membranes
using standard procedures (23)
. Membranes were then washed
three times (5 min each) with TBS-T containing 3% milk, incubated with
primary antibody (27D6/20 MoAb), diluted in the same buffer (1 µg/ml)
for a minimum of 2 h at room temperature, washed again as outlined
above (three times, 5 min each), and then incubated with antimouse
horseradish peroxidase-conjugated secondary antibody for 1 h.
Membranes were subsequently washed (three times, 5 min each) with
TBS-T/milk and then washed once with 0.5% TBS-T and washed twice with
50 mM Tris (pH 6.8). The optimal primary antibody
dilution was determined by titrating 27D6/20 MoAb against GST-TCL1
fusion protein. Antigen-antibody interaction was detected by enhanced
chemiluminescence (Amersham, Arlington Heights, IL).
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. Expression analysis performed in spleen tissues showed
that cells of the MaZ were consistently TCL1 negative (Fig. 1B)
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and follicular lymphomas (Fig. 1C)
, in
all cases of lymphocytic lymphoma/CLL (Fig. 1F)
, in all but
one case of mantle cell lymphoma (Fig. 1G)
, in 60% of nodal
diffuse large B-cell lymphomas (Fig. 1H)
, in 100% of BLs
(Fig. 1I)
, in 60% of primary cutaneous follicle center cell
lymphomas, and in 50% of PCBCLs other than follicular lymphoma.
TCL1 was not expressed in nodal and extranodal MaZ cell
lymphomas (including MALT-L) or in neoplastic plasma cells in all seven
cases of multiple myeloma and all five cases of extramedullary
plasmacytoma (Table 1)
. The percentage of positive cells and the degree
and pattern (nuclear and/or cytoplasmic) of immunoreactivity were
somewhat variable in the different subtypes of lymphoproliferative
diseases, with well-differentiated lymphocytic lymphoma/CLL, mantle
cell lymphoma, and BL usually showing a higher percentage of positive
cells, which is often associated with a stronger
immunoreactivity. On the contrary, follicular lymphoma and
diffuse large B-cell lymphoma cases showed a more variable distribution
in terms of the number of positive cells and the degree of
immunoreactivity. As far as the immunolocalization of TCL1 is
concerned, in most cases, we observed both nuclear and
cytoplas- mic immunoreactivity, with only a minority of cases of
diffuse large B-cell lymphoma and BL showing either nuclear or
cytoplasmic immunoreactivity. These findings are shown in Fig. 1, A–N.
HD and CD30+ Anaplastic Large Cell Lymphoma.
Twenty cases of classical HD [14 cases of the nodular sclerosis
variant (Fig. 1D)
and 6 cases of the mixed cellularity
variant] have been investigated. In all of these cases, the
Hodgkin/Reed-Sternberg cells were consistently TCL1 negative.
Areas/nodules and scattered, TCL1-positive, small lymphoid cells were
observed in all cases. Furthermore, in those cases in which residual
lymphoid follicles with GCs were present, the pattern of TCL1
immunoreactivity was similar to that observed in the follicles of
reactive lymphoid hyperplasia. Five cases of nodular lymphocyte
predominance HD have been studied. In all cases, the "pop corn"
Reed-Sternberg cells typical of nodular lymphocyte predominance
HD were consistently TCL1 negative (Fig. 1E)
. In all cases,
the nodules developed from progressively transformed GCs contained a
significant number of TCL1-positive, small lymphoid cells.
Five cases of CD30+ anaplastic large cell
lymphoma have been studied, and all of them were consistently TCL1
negative (Table 1)
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T-cell Lymphomas.
Five cases of T-cell lymphoblastic lymphoma, 10 cases of nodal
peripheral T-cell lymphoma, and 40 cases of primary cutaneous T-cell
lymphoma have also been investigated, and all of them were consistently
TCL1 negative. In every case, scattered, TCL1-positive, small lymphoid
cells were present. In those cases in which residual lymphoid follicles
were observed, TCL1 immunoreactivity was similar to that observed in
the follicles of reactive lymphoid hyperplasia (Fig. 1A)
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FACS Analysis on PBMCs from Normal Donors and from a T-PLL Patient.
To assess whether the MoAb 27D6/20 was also a valuable tool in FACS
analysis, we analyzed permeabilized PBMCs derived from normal donors
and from one case of T-PLL. FACS analysis revealed that TCL1 is
expressed in CD19+ cells, but no TCL1 expression
is detectable in CD3+ cells of normal donors
(Fig. 2, A and B)
. Conversely, FACS analysis performed on
cells from a 75-year-old T-PLL patient (high WBC count, splenomegaly,
>90% of circulating T lymphocytes with a T mature phenotype,
CD3+, TCR
ß+,
TCR
-, CD4+,
CD8-, CD2+,
CD5+, CD7+,
CD25+/-, CD16-,
CD56-, and CD19-)
revealed a strong TCL1 expression in these lymphocytes (Fig. 2C)
, confirming that TCL1 is directly activated as described
previously by other methods (9
, 24)
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, in which the MoAb recognizes only an approximately
Mr 14,000 protein in cell
extracts derived from the SUPT11 cell line on Western blot analysis.
Furthermore, the 27D6/20 antibody is specific to recombinant TCL1
protein and does not cross-react with the recombinant TCL1b gene
product and MTCP1 (Fig. 3A)
. The localization of TCL1 to
both the cytoplasm and nuclear fractions was confirmed by immunoblots
of subcellular fractions from SUPT11 cells. As shown in Fig. 3B
, TCL1 is present in both the cytoplasm and isolated
nuclei. The distribution of TCL1 between the two compartments is not
equivalent, and a densitometer quantification shows a distribution
ratio of 1:7 between the nucleus and cytoplasm. Effective
separation of nuclei from cytoplasm has been confirmed by immunoblots
for ß-tubulin, which show that isolated nuclei are devoid of
cytoskeletal and cytoplasmic contamination (Fig. 3B)
. TCL1
localization to both the cytoplasm and nucleus is also shown in high
magnification of an immunohistochemistry performed on reactive lymph
node tissue (Fig. 1N)
.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. TCL1 expression studies have been conducted predominantly in bone
marrow and thymic fetal cells, normal and malignant B- and T-cell
lines, T-cell leukemias, and peripheral blood primarily by reverse
transcription-PCR and Northern blotting (3
, 8
, 9
, 15
, 16)
,
and, using molecular analysis and immunocytochemistry, Teitell et
al. (25)
recently reported TCL1 involvement in
reactive tonsils and lymph nodes and TCL1 up-regulation in the majority
of AIDS immunoblastic lymphoma plasmacytoid tumors examined.
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TCL1 was observed in only 55% of PCBCLs, but it was not observed in the remaining 45% of PCBCLs, suggesting that this subset of lymphomas could originate from B cells in an advanced stage of differentiation (post-GC) and supporting the recent proposal that histological subtypes of PCBCLs could be derived from MaZ B cells (30 , 31) .
The expression pattern depicted above was also reflected in the staining of normal reactive lymph nodes and spleen. TCL1 expression was highly positive in a subset of mantle zone small lymphocytes, mainly within the nucleus. Centroblasts and centrocytes of the GC showed a lesser and more variable TCL1 expression ranging from slight to moderate, with both nuclear and cytoplasmic localization. TCL1 expression was consistently negative in the MaZ cells of the normal spleen follicles. Our results are consistent with the recent findings of Teitell et al. (25) , who reported that hyperplastic lymph node and tonsil also exhibit strong TCL1 protein expression in mantle zone B cells and in rare interfollicular zone cells, whereas follicle-center B-cells show weaker expression.
Analysis of T-cell neoplasms, including nodal, cutaneous, and T-cell lymphomas and CD30+ anaplastic large cell lymphoma, revealed no TCL1 expression except in a T-PLL, in which TCL1 plays a causative role.
The pattern of immunoreactivity of TCL1 in B cells showed that TCL1 is detectable within both the nuclei and cytoplasm. Moreover, the nuclear immunoreactivity appears moderately strong in some B cells, such as in the subset of mantle B lymphocytes. These results, together with new data obtained concerning the protein structure (13 , 14) , suggest a possible active role for TCL1 as a "shuttle protein" between the cytoplasm and the nucleus.
Whereas its function has yet to be unraveled, TCL1 and its cognate,
MTCP1, and probably TCL1b as well are clearly involved in lymphoid
tumorigenesis and differentiation; antiapoptotic activity might be
envisaged, based on the long latency of the tumors associated with
TCL1/MTCP1 expression in ataxia telangiectasia patients (9
, 24)
and transgenic mice (11
, 12)
and on TCL1
expression, which seems to parallel that of BCL-2 (25)
.
However, although it is evident that TCL1 is predominately expressed in
quiescent mantle zone B cells, no reactivity is observed in most normal
T cells, plasma cells, and MaZ cell lymphoma as seen with BCL-2
(32)
; therefore, it is possible that TCL1 might
also act on a pathway other than BCL-2-associated apoptosis. At the
moment, its window of expression in normal and pathological B
lymphocytes, excluding the possibility that specific chromosomal
translocations could activate it, suggests its involvement in B-cell
differentiation and highlights the observation that this gene is highly
expressed in antigen-committed B cells, persists in antigen-activated
GC B cells, and is down-regulated in the latest stage of B-cell
differentiation (Fig. 4)
.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by Associazione Italiana per
la Ricerca sul Cancro, Telethon Grant D102, Ministero Italiano della
Sanità, and Ministero dell’Università e Ricerca
Scientifica e Tecnologica. M. G. N. and E. P. contributed equally to
this work. 
2 To whom requests for reprints should be
addressed, at IDI-IRCCS, Research Laboratories, Via Monti di
Creta 104, Rome 00161, Italy. Phone: 39-06-66462432; Fax:
39-06-66462430; E-mail: russo{at}idi.it
3 The abbreviations used are: TCR, T-cell
receptor; Ig, immunoglobulin; GC, germinal center; T-PLL,
T-prolymphocytic leukemia; FACS, fluorescence-activated cell sorting;
HD, Hodgkin’s disease; MaZ, marginal zone; MALT-L, mucosa-associated
lymphoid tissue lymphoma; PCBCL, primary cutaneous B-cell lymphoma, BL,
Burkitt lymphoma; MoAb, monoclonal antibody; T-ALL, T-acute lymphatic
leukemia; TBS-T, Tris-buffered saline; GST, glutathione
S-transferase; CLL, chronic lymphocytic leukemia; PBMC,
peripheral blood mononuclear cell; DLBCL, diffuse large B-cell
lymphoma; MCL, mantle cell lymphoma; FL, follicular lymphoma.
Received 12/ 6/99. Accepted 3/ 2/00.
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/ locus in mature T cell proliferations. Oncogene, 8: 2475-2483, 1993.[Medline]
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