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IMMUNOBIOLOGY
From the Institute of Medical Microbiology and
Immunology and the Institute of Medical Anatomy, Section A, University
of Copenhagen, Denmark; the Department of Immunology, Osaka City
Medical School, Japan; and Institute of Human Genetics, University of
Aarhus, Denmark.
Mycosis fungoides is a low-grade cutanous T-cell lymphoma
(CTCL) of unknown etiology. In advanced stages of CTCL, a shift in
cytokine profile from TH1 to TH2 is observed,
which coincides with eosinophilia, high levels of immunoglobulin E, and
increased susceptibility to bacterial infections. It is, however,
unknown why TH2 cytokines predominate in advanced CTCL, and
the cellular source of these cytokines also remains to be identified.
In several leukemias and lymphomas, constitutively activated signal
transducer and activator of transcription (Stat) signaling pathways
have been detected. In a previous study, constitutive activation of Stat3 was found in tumor cells isolated from affected skin and blood
from CTCL patients. Here, it is shown that CTCL tumor cell lines, but not nonmalignant cell lines, spontaneously produce interleukin-5 (IL-5), IL-6, and IL-13. Transfection of tumor cells with
dominant-negative Stat3 almost completely blocks IL-5 production and
strongly inhibits IL-13 production, whereas IL-6 production is
unaffected. Thus, the data show that malignant CTCL cells themselves might contribute to the change in cytokine pattern accompanying progression of CTCL. In conclusion, constitutively activated Stat3 is
found to mediate a spontaneous IL-5 production and regulate IL-13
production in CTCL cell lines, pointing toward a new role of Stat3 in
malignant transformation.
(Blood. 2002;99:973-977) Cutanous T-cell lymphomas (CTCLs) are a
heterogeneous group of lymphomas, of which mycosis fungoides (MF) and
the leukemic variant Sézary syndrome (SS) are the most common
(reviewed in Samuelson,1 Diamandidou et al2).
Although viral transformation with human T-cell lymphotropic virus type
1 has been found in some cases of CTCL,3 it does
not seem to be the agent causing MF.4 Thus, the primary
etiology of MF remains to be found. In the initial phase, which can
endure for several years, MF is found as flat erythromatous skin
lesions, resembling nonmalignant psoriasis or eczema. In later stages,
tumor cells spread to other sites of the body with a fatal outcome. In
SS, the leukemic form of MF, tumor T cells are present both in the skin
and in the blood.1
Previously, several groups have investigated cytokine production in
skin lesions or peripheral blood from CTCL patients to establish
whether a unique cytokine profile could be associated with the disease.
Although the results of these studies have not been entirely
concordant, the general concept is that a shift in cytokine profile
from TH1 to TH2 accompanies disease
progression. In a report by Vowels et al,5 expression of
TH2 cytokine messenger RNA (mRNA) was found to correlate
with disease progression. In a study by Lee et al,6 an
inability of T cells to produce interferon In CTCL patients, as well as many other lymphoma patients, concomitant
eosinophilia, elevated levels of immunoglobulin (Ig)-E and IgA, and
decreased cell-mediated immunity are often observed.10,11 These complications could be caused by a shift in the cytokine pattern
from a TH1-like to a TH2-like profile that
accompanies progression of CTCL. In this regard, interleukin-5 (IL-5)
is the predominant regulator of eosinophilia12 and has
been shown to play an important role in the development of eosinophilia
in Hodgkin disease.13 Likewise, cytokines such as IL-4,
IL-10, and IL-13 stimulate antibody production and hence favor humoral
immune responses at the expense of cellular immune responses that are
needed to eliminate the tumor.12
Signal transducer and activator of transcription (Stat) proteins
compose a family of transcription factors activated in response to most
cytokines and growth factors. Upon receptor ligation, Stat proteins are
activated by tyrosine phosphorylation mediated by receptor-associated
Jak kinases. Following tyrosine phosphorylation, Stats dimerize and
translocate to the nucleus, where they act directly as activators of
transcription (reviewed in Imada and Leonard14). It was
previously found that a member of the Stat family, Stat3, is
constitutively activated in tumor cells from MF and
SS15-17 and mediates the expression of constitutive
suppressors of cytokine signaling-3.18 Recently, Stat3
was found to function as an oncogene,19 but the mechanism
underlying its oncogenic effect is not yet clear.
Here, we have investigated cytokine production in tumor cell lines
established from affected skin and blood from patients with CTCL. We
show that malignant T cells produce TH2 cytokines such as
IL-5 and IL-13. Furthermore, we demonstrate that IL-5 (and to some
extent IL-13) production in MF tumor cells is mediated by
constitutively activated Stat3.
Antibodies and other reagents
Cells
Transfection of MF tumor cells Expression vectors pCAGGSneo-HA-Stat3 wild type (WT) or pCAGGSneo-HA-Stat3 dominant negative (D) have been described previously.25 In Stat3D, E434 and E435 have been replaced with alanines, rendering Stat3D unable to bind DNA. Stable transfections of MF2000 cells were performed by electroporation (240 V) using 25 µg DNA. Transfected cells were selected in medium containing 1.5 mg/mL Geneticin (G-418 sulfate) (Gibco), and expression of "exogeneous" Stat3 was examined by Western blotting with HA antibody.RNAse protection assay RNA extraction was performed by means of the QIA shredder and RNeasy Mini Kits from Qiagen (Valencia, CA) as described.26 The purity and size distribution of total RNA were determined by agarose gel electrophoresis. RNase protection assay was performed by means of the ribonuclease protection assay kit and the in vitro transcription kit from Pharmingen according to the manufacturer's protocol.Enzyme-linked immunosorbent assay Before the ELISA, cells were washed and incubated overnight in fresh medium at 1 × 106 cells per milliliter. The cytokine production was analyzed by sandwich ELISA with the use of the manufacturer's protocol (Pharmingen/BectonDickinson).Oligonucleotide affinity purification of Stat proteins and Western blotting Cells were lysed in ice-cold lysis buffer (1% NP-40; 20 mM Tris, pH 8.0; 137 mM NaCl; 5 mM MgCl2; 10% glycerol; and the following inhibitors: 5 mM EDTA, 1 mM Na3VO4, 10 µg/mL aprotinin, 4 µM iodoacetamide, 1 mM phenylmethyl sulfonyl fluoride). For oligonucleotide affinity purification, 150 pmol double-stranded biotinylated oligo was added to the cell lysate and incubated 2 hours. Stat/oligonucleotide complexes were recovered by means of streptavidin-conjugated beads. Purified proteins or total lysates were boiled in reducing sodium dodecyl sulfate sample buffer and analyzed by gel electrophoresis followed by electrophoretic transfer to a nitrocellulose membrane. The membrane was blocked in 3% skim milk and 1% bovine serum albumin in phosphate-buffered saline (PBS) and incubated with primary antibody in blocking buffer followed by washing in PBS and incubation with peroxidase-conjugated secondary antibody. Blots were evaluated by means of enhanced chemiluminescence, stripped, and reprobed as described (Amersham, Buckinghamshire, United Kingdom).27
CTCL tumor cells produce TH2 cytokines To evaluate cytokine expression in CTCL, we first examined production of classical TH1 (IFN- ) and TH2
(IL-4, IL-5, and IL-13) cytokines in MF tumor T cells and nonmalignant
T cells isolated from the same patient. MF2000 is a continuous tumor
cell line, established from a plaque biopsy from a patient with
classical MF, that has all the malignant characteristics of
MF.22 As shown in Table 1,
MF2000 did not produce any IFN- or IL-4, whereas high amounts of
both IL-5 and IL-13 were detected. In contrast, the nonmalignant cell
line, MF1885, produced neither IFN-, IL-4, nor IL-5 and produced
only barely detectable amounts of IL-13. To further clarify whether
production of the TH2 cytokines IL-5 and IL-13 is a general
phenomenon in tumor cells from CTCL, an early culture of MF tumor cells
(MF3675) as well as an SS (SeAx) tumor cell line were examined. As
shown in Figure 1, all the tumor cell
lines produced IL-5 and IL-13, although MF3675 did so to a lesser
extent than MF2000. In a further ELISA screening for IL-2, IL-6, IL-7,
IL-12, IL-14, IL-15, and tumor necrosis factor  production, only
IL-6 was detected in MF2000 supernatants (data not shown).
Treatment with a Jak3 inhibitor inhibits IL-5 and IL-13 production in CTCL tumor cells It was previously shown that SS and MF tumor cells express constitutively activated Stat3.15,16 Here, we addressed whether the constitutive Stat3 activation is involved in (dys)regulation of cytokine production in CTCL cells. As shown previously,16,28 and confirmed here, treatment of SS and MF tumor cells with tyrphostin Ag490, an inhibitor of Jak kinases, inhibits constitutive Stat3 activation (Figure 2A). By means of RNAse protection assay, the effect of Ag490 incubation on cytokine mRNA was examined (Figure 2B). Interestingly, expression of both IL-5 and IL-13 mRNA was strongly inhibited in both cell lines following treatment with Ag490. In contrast, mRNA for the housekeeping genes L32 and GADPH was not affected, indicating that it is a specific rather than a toxic effect of Ag490. To see whether the effect of Ag490 detected at the mRNA level was also evident at the protein level, ELISA assays for IL-5, IL-6, and IL-13 were performed. Because Jak3 is constitutively activated and/or associated with Stat3 in CTCL,15,17 a more selective inhibitor of Jak3 (Jak3-II) was also included in this experiment. As shown in Figure 2C, both IL-5 and IL-13 production were strongly inhibited by both Jak kinase inhibitors, in particular by the more selective Jak3-II inhibitor, which inhibited cytokine production by approximately 90%. In contrast, IL-6 production was not as strongly inhibited. PP1, an inhibitor of src kinases, did not have any effect on the production of any of the cytokines. Although Jak inhibitors might also inhibit Jak targets other than activated Stat3, these data suggest that constitutive active Stat3 might be involved in the disordered cytokine production in CTCL tumor cell lines.
Transfection of MF tumor cells with dominant-negative Stat3 To investigate the role of constitutive Stat3 activation in cytokine production in a more direct way, we stably transfected MF tumor cells with either WT or dominant-negative (D) HA-tagged Stat3. Stat3D contains mutations at positions important for DNA binding.25 The expression level of transfected Stat3 was determined by blotting with antibody against the HA tag (Figure 3A). In the following experiments, 3 Stat3WT (WT6.2, WT6.8, WT6.12) and 3 Stat3D (D1, D4, D14) transfectants were used. It was a consistent finding that Stat3D transfectants had a higher expression level of exogenous Stat3 than WT transfectants. To examine the dominant-negative effect of Stat3D, transfectants were stimulated with IFN-, which is a strong
inducer of Stat3 activation. Hereafter, binding to hSIE, an oligo
representing a Stat-binding sequence from the c-fos promotor, was
analyzed by affinity purification of proteins binding to the oligo. As
shown in Figure 3B (upper panel), there was a constitutive background
level of Stat3 binding to DNA in unstimulated Stat3WT cells, analogous
to our previous findings.15 Upon IFN- stimulation for
15 minutes, DNA binding was further increased and declined after
45 minutes to background level. In contrast, constitutive DNA binding
of Stat3 in Stat3D cells was strongly reduced and was only marginally
induced by IFN-. Aliquots of the lysates used to study DNA binding
were blotted with antibody against tyrosine-phosphorylated Stat3
(PY-Stat3) (Figure 3B, middle panel) to demonstrate that tyrosine
phosphorylation of Stat3 was not inhibited. Reblotting the membrane
with Stat3 antibody confirmed that the blocked DNA binding was not due
to unequal amounts of protein in the samples (Figure 3B, lower panel).
To ensure that other Stat signaling pathways were not affected,
transfected cells were stimulated with IL-4 in order to examine Stat6
activation. As shown in Figure 3C (upper panel), DNA binding of Stat6
was equally well induced in Stat3WT and Stat3D cells. Likewise,
blotting of total lysates demonstrated identical induction of Stat6
tyrosine phosphorylation (middle panel) and equal amounts of Stat6 in
the samples (bottom panel). Thus, transfection of MF cells with Stat3D selectively inhibits constitutive active Stat3 in a
dominant-negative manner.
IL-5 production in MF tumor cells is mediated through constitutively activated Stat3 Production of IL-5, IL-6, and IL-13 was examined in 3 Stat3WT lines (WT6.2, WT6.8, WT6.12) and 3 Stat3D lines (D1, D4, D14). As shown in Figure 4, the spontaneous production of IL-5 was totally blocked in all Stat3D transfectants, demonstrating that constitutively active Stat3 plays a major role in IL-5 production in MF tumor cells. In contrast, there was no difference in IL-6 production between Stat3WT and Stat3D cells. As regards IL-13 production, Stat3 seemed to be partially involved, since cytokine levels decreased to about 30% to 40% in Stat3D transfectants compared with Stat3WT. A comparison of the transfectant studies in which Stat3 was specifically inhibited (Figure 4) with experiments using Jak inhibitors (Figure 2B-C) makes it evident that blocking Jak kinase activity affects targets other than Stat3, since Jak inhibition influenced IL-6 production whereas specific inhibition of Stat3 did not.
In the present study, we provide the first evidence that CTCL tumor cell lines, but not an autologous nonmalignant T-cell line, spontaneously produce high amounts of IL-5, IL-6, and IL-13. Production of TH2-like cytokines, such as IL-5 and IL-13, might promote disease progression, since TH2 cytokines have a negative influence on antitumor immune responses. Moreover, secretion of IL-5 and IL-13 could be involved in the complications that often follow CTCL such as eosinophilia, erythroderma, and elevated titers of IgE, since it is well known that IL-5 is one of the main controlling cytokines for eosinophilia and IL-13 induces IgE synthesis in B cells. Catovsky et al11 found that eosinophil counts fell during remission and rose during relapse in patients with T-lymphoblastic lymphomas, supporting the idea that eosinophilia could be induced by cytokines produced by the malignant cells. Experiments using inhibitors of Jak kinases suggested that constitutively activated Stat3 might be involved in the production of IL-5 and IL-13, as inhibition of Stat3 was followed by decreased production of these cytokines. However, this indirect way of inhibiting Stat3 might also affect other Jak3 targets. Therefore, in order to address the question in a more direct way, we investigated cytokine production in MF tumor cells stably transfected with dominant-negative Stat3. These studies provided strong evidence that constitutive Stat3 activation plays a major role in inducing IL-5 production in MF tumor cells and is involved in regulation of IL-13 production. In contrast, constitutive activation of Stat3 was found to be not involved in IL-6 production. The importance of Stat3 in IL-5 production might also be reflected in the finding that MF3675 has a lower production of IL-5 than MF2000, since MF3675 cells have a lower level of constitutive Stat3 activation than MF2000 (Figure 1 and data not shown). Whether Stat3 induces IL-5 transcription directly or via a secondary mechanism is not clear at the moment. Although IL-5 synthesis is known to be regulated at the transcriptional level, only limited information about the promotor sequence is available. However, some important regulatory elements have been reported (ie, Cle0, REI, II, III).29,30 We searched these promotor sequences for Stat3-binding sites, but failed to identify any sequences that could actually bind Stat3 in experiments using MF tumor cells. Although we cannot exclude the possibility that a Stat3-binding motif could be present in the IL-5 promotor, these findings might suggest that Stat3 mediates IL-5 production via an indirect mechanism. Blocking experiments with cytokine and cytokine receptor antibodies have indicated that IL-5 production is not induced by IL-6 or IL-13 (or vice versa; data not shown). Likewise, the constitutive activation of Stat3 is not induced via an autocrine loop involving these cytokines (data not shown). As mentioned above, IL-5 has been associated with eosinophilia and the clinical syndrome erythroderma. In this respect, it should be noted that all cell lines used in this study were obtained from patients suffering from severe erythoderma. It has been proposed that in Hodgkin disease IL-5 is a key mediator of eosinophilia,13 and studies are now in progress to elucidate whether Stat3 is also involved in IL-5 production in Hodgkin disease and other lymphomas. In conclusion, constitutively activated Stat3 mediates a spontaneous IL-5 production and regulates IL-13 production in CTCL cell lines, pointing toward a new role of Stat3 in malignant transformation. Thus, Stat3 might be a highly relevant target for therapeutical intervention in CTCL.
Submitted April 2, 2001; accepted September 27, 2001.
Supported in part by The Weimann Foundation (M.N.), The Foundation of 17/12-1981 (J.G.), The Danish Medical Research Council, The Danish Biotechnological Center for Cellular Communication, The Carlsberg Foundation, The Novo Nordic Foundation, The Danish Medical Associations Research Foundation (Lægeforeningens Forskningsfond), The Danish Cancer Research Foundation (Dansk Kræftforsknings fond), and The Danish Cancer Society (Kræftens Bekæmpelse).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Niels Ødum, Institute of Medical Microbiology and Immunology, University of Copenhagen, Panum 22.5, Blegdamsvej 3, 2200 Copenhagen N, Denmark; e-mail: n.odum{at}immi.ku.dk.
1. Samuelson E. Cutaneous T-cell lymphomas. Semin Oncol Nurs. 1998;14:293-301[CrossRef][Medline] [Order article via Infotrieve].
2.
Diamandidou E, Cohen PR, Kurzrock R.
Mycosis fungoides and Sezary syndrome.
Blood.
1996;88:2385-2409
3.
Manca N, Piacentini E, Gelmi M, et al.
Persistence of human T cell lymphotropic virus type 1 (HTLV-1) sequences in peripheral blood mononuclear cells from patients with mycosis fungoides.
J Exp Med.
1994;180:1973-1978 4. Li G, Vowels B, Benoit BM, Rook AH, Lessin SR. Failure to detect human T-lymphotropic virus type-I proviral DNA in cell lines and tissues from patients with cutaneous T-cell lymphoma. J Invest Dermatol. 1996;107:308-313[CrossRef][Medline] [Order article via Infotrieve]. 5. Vowels BR, Lessin SR, Cassin M, et al. Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma. J Invest Dermatol. 1994;103:669-673[CrossRef][Medline] [Order article via Infotrieve].
6.
Lee BN, Duvic M, Tang CK, Bueso-Ramos C, Estrov Z, Reuben JM.
Dysregulated synthesis of intracellular type 1 and type 2 cytokines by T cells of patients with cutaneous T-cell lymphoma.
Clin Diagn Lab Immunol.
1999;6:79-84 7. Harwix S, Zachmann K, Neumann C. T-cell clones from early-stage cutaneous T-cell lymphoma show no polarized Th-1 or Th-2 cytokine profile. Arch Dermatol Res. 2000;292:1-8[CrossRef][Medline] [Order article via Infotrieve]. 8. Yamamoto T, Sasaki G, Sato T, Katayama I, Nishioka K. Cytokine profile of tumor cells in mycosis fungoides: successful treatment with intralesional interferon-gamma combined with chemotherapy. J Dermatol. 1995;22:650-654[Medline] [Order article via Infotrieve].
9.
Poszepczynska E, Bagot M, Echchakir H, et al.
Functional characterization of an IL-7-dependent CD4(+)CD8alphaalpha(+) Th3-type malignant cell line derived from a patient with a cutaneous T-cell lymphoma.
Blood.
2000;96:1056-1063
10.
Chan LS, Hanson CA, Cooper KD.
Concurrent eosinophilic fasciitis and cutaneous T-cell lymphoma: eosinophilic fasciitis as a paraneoplastic syndrome of T-cell malignant neoplasms?
Arch Dermatol.
1991;127:862-865 11. Catovsky D, Bernasconi C, Verdonck PJ, et al. The association of eosinophilia with lymphoblastic leukaemia or lymphoma: a study of seven patients. Br J Haematol. 1980;45:523-534[Medline] [Order article via Infotrieve]. 12. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145-173[CrossRef][Medline] [Order article via Infotrieve]. 13. Di Biagio E, Sanchez-Borges M, Desenne JJ, Suarez-Chacon R, Somoza R, Acquatella G. Eosinophilia in Hodgkin's disease: a role for interleukin 5. Int Arch Allergy Immunol. 1996;110:244-251[Medline] [Order article via Infotrieve]. 14. Imada K, Leonard WJ. The Jak-STAT pathway. Mol Immunol. 2000;37:1-11[CrossRef][Medline] [Order article via Infotrieve].
15.
Nielsen M, Kaltoft K, Nordahl M, et al.
Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of MF tumor cell lines.
Proc Natl Acad Sci U S A.
1997;94:6764-6769 16. Eriksen KW, Kaltoft K, Mikkelsen G, et al. Constitutive Stat3-activation in Sezary syndrome: tyrphostin AG-490 inhibits Stat3-activation, interleukin-2 receptor expression and growth of a leukemic Sezary cell line. Leukemia. 2001;15:787-793[CrossRef][Medline] [Order article via Infotrieve].
17.
Zhang Q, Nowak I, Vonderheid EC, et al.
Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutanous anaplastic large T-cell lymphoma and Sezary syndrome.
Proc Natl Acad Sci U S A.
1996;93:9148-9153
18.
Brender C, Nielsen M, Kaltoft K, et al.
STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma.
Blood.
2001;97:1056-1062 19. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell. 1999;98:295-303[CrossRef][Medline] [Order article via Infotrieve].
20.
Shen CH, Stavnezer J.
Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription.
Mol Cell Biol.
1998;18:3395-3404 21. Wagner BJ, Hayes TE, Hoban CJ, Cochran BH. The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter. EMBO J. 1990;9:4477-4484[Medline] [Order article via Infotrieve]. 22. Kaltoft K, Bisballe S, Dyrberg T, Boel E, Rasmussen PB, Thestrup-Pedersen K. Establishment of two continuous T-cell strains from a single plaque of a patient with mycosis fungoides. In Vitro Cell Dev Biol. 1992;28A:161-167[CrossRef]. 23. Kaltoft K, Hansen BH, Thestrup-Pedersen K. Cytogenetic findings in cell lines from cutaneous T-cell lymphoma. Dermatol Clin. 1994;12:295-304[Medline] [Order article via Infotrieve]. 24. Kaltoft K, Bisballe S, Rasmussen HF, Thestrup-Pedersen K, Thomsen K, Sterry W. A continuous T-cell line from a patient with Sezary syndrome. Arch Dermatol Res. 1987;279:293-298[CrossRef][Medline] [Order article via Infotrieve]. 25. Nakajima K, Yamanaka Y, Nakae K, et al. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J. 1996;15:3651-3658[Medline] [Order article via Infotrieve]. 26. Brender C, Nielsen M, Ropke, et al. Interferon-alpha induces transient suppressors of cytokine signalling expression in human T cells. Exp Clin Immunogenet. 2001;18:80-85[CrossRef][Medline] [Order article via Infotrieve]. 27. Eriksen KW, Nielsen M, Kaltoft K, et al. Oligonucleotide fishing for Stat6: cross-talk between IL4 and chemokines. Exp Clin Immunogenet. 2001. In press. 28. Nielsen M, Kaestel CG, Eriksen KW, et al. Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells. Leukemia. 1999;13:735-738[CrossRef][Medline] [Order article via Infotrieve]. 29. Thomas MA, Mordvinov VA, Sanderson CJ. The activity of the human interleukin-5 conserved lymphokine element 0 is regulated by octamer factors in human cells. Eur J Biochem. 1999;265:300-307[Medline] [Order article via Infotrieve].
30.
Stranick KS, Zambas DN, Uss AS, Egan RW, Billah MM, Umland SP.
Identification of transcription factor-binding sites important in the regulation of the human interleukin-5 gene.
J Biol Chem.
1997;272:16453-16465
© 2002 by The American Society of Hematology.
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  M. Marzec, K. Halasa, M. Kasprzycka, M. Wysocka, X. Liu, J. W. Tobias, D. Baldwin, Q. Zhang, N. Odum, A. H. Rook, et al. Differential Effects of Interleukin-2 and Interleukin-15 versus Interleukin-21 on CD4+ Cutaneous T-Cell Lymphoma Cells Cancer Res., February 15, 2008; 68(4): 1083 - 1091. [Abstract] [Full Text] [PDF]
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 A. Woetmann, P. Lovato, K. W. Eriksen, T. Krejsgaard, T. Labuda, Q. Zhang, A.-M. Mathiesen, C. Geisler, A. Svejgaard, M. A. Wasik, et al. Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins Blood, April 15, 2007; 109(8): 3325 - 3332. [Abstract] [Full Text] [PDF]
|
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 |
|
 E. Tancrede-Bohin, M. A. Ionescu, P. de La Salmoniere, A. Dupuy, J. Rivet, M. Rybojad, L. Dubertret, H. Bachelez, C. Lebbe, and P. Morel Prognostic Value of Blood Eosinophilia in Primary Cutaneous T-Cell Lymphomas Arch Dermatol, September 1, 2004; 140(9): 1057 - 1061. [Abstract] [Full Text] [PDF]
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C. Guiter, I. Dusanter-Fourt, C. Copie-Bergman, M.-L. Boulland, S. le Gouvello, P. Gaulard, K. Leroy, and F. Castellano Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma Blood, July 15, 2004; 104(2): 543 - 549. [Abstract] [Full Text] [PDF]
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 M. Girardi, P. W. Heald, and L. D. Wilson The Pathogenesis of Mycosis Fungoides N. Engl. J. Med., May 6, 2004; 350(19): 1978 - 1988. [Full Text] [PDF]
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Top
Abstract
Introduction
1.
