Blood, 1 May 2002, Vol. 99, No. 9, pp. 3488-3489
CORRESPONDENCE
To the editor:
The role of interleukin-7 and interleukin-15 in cutaneous
T-cell lymphoma
Elucidation of any mechanism underlying neoplastic
proliferation is welcome news. The article by Qin et al was no
exception.1 The authors have clearly demonstrated, as well
as confirmed,2 that interleukin-7 (IL-7) and IL-15
regulate the expression of bcl-2 and c-myb
genes in cutaneous T-cell lymphoma (CTCL). It was
disappointing to note, however, that Qin et al appear to be completely
unaware of the underlying stimulus, which initiates the proliferation
machinery in the first place. It has been recognized for some time that
practically all patients with CTCL carry human T-cell lymphotropic
virus-1 (HTLV-I) Tax in their circulating and skin-infiltrating
lymphocytes.3,4 Such patients also have Tax mRNA and
antibodies to p40 Tax, the gene product of this sequence.5,6 In addition, it has been shown that IL-15
overexpression is attributable, specifically, to Tax transactivation of
its promoter, as well as other NFkB transcription factors (reviewed in
Gitlin et al7). Therefore, while the data presented by Qin
et al are not disputed, the report would have been more meaningful if
the underlying cause for the upregulation of IL-7 and IL-15 had not been ignored. Such information not only is of cursory interest but also
may have therapeutic implications since it has already been shown that
the in vitro proliferation of CTCL cells can be inhibited with
antisense to Tax.8
Dorothea Zucker-Franklin
Correspondence: New York University School of Medicine, 550 First Ave, New York, NY 10016
References
1.
Qin J-Z, Zhang C-L, Kamarashev J, et al.
Interleukin-7 and interleukin-15 regulate the expression of the bcl-2 and c-myb genes in cutaneous T-cell lymphoma cells.
Blood.
2001;98:2778-2783[Abstract/Free Full Text].
2.
Mariner JM, Lantz V, Waldmann TA, Azimi N.
Human T cell lymphotropic virus type I Tax activates IL-15R alpha gene expression through an NF-kappa B site.
J Immunol.
2001;166:2602-2609[Abstract/Free Full Text].
3.
Pancake BA, Zucker-Franklin D, Coutavas E.
The cutaneous T cell lymphoma mycosis fungoides is a T cell lymphotropic virus associated disease: a study of 50 patients.
J Clin Invest.
1995;95:547-554.
4.
Khan ZM, Sebenik M, Zucker-Franklin D.
Localization of human T-cell lymphotropic virus-1 tax proviral sequences in skin biopsies of patients with mycosis fungoides by in situ polymerase chain reaction.
J Invest Dermatol.
1996;106:667-672[CrossRef][Medline]
[Order article via Infotrieve].
5.
Pancake BA, Wassef F, Zucker-Franklin D.
Demonstration of antibodies to HTLV-I tax in patients with cutaneous T cell lymphoma mycosis fungoides, who are seronegative for antibodies to the structural proteins of the virus.
Blood.
1996;88:3004-3009[Abstract/Free Full Text].
6.
Zucker-Franklin D, Pancake BA, Marmor M, Legler PM.
Reexamination of human T cell lymphotropic virus (HTLV-I/II) prevalence.
Proc Nat Acad Sci U S A.
1997;94:6403-6407[Abstract/Free Full Text].
7.
Gitlin SD, Dittmer J, Reid RL, et al.
The molecular biology of human leukemia virus. In:
Cullen BR, ed.
Human Retroviruses. New York, NY: Oxford University Press; 1993:159-162.
8.
Zucker-Franklin D.
The role of human T cell lymphotropic virus Type I Tax in the development of cutaneous T cell lymphoma.
Ann NY Acad Sci.
2001;941:86-96[Abstract/Free Full Text].
Response:
Why human T-cell lymphotropic virus-1 Tax is not the cause of
cutaneous T-cell lymphoma
Dr Zucker-Franklin claims that the human T-cell lymphotropic
virus-1 (HTLV-I) Tax protein is the main stimulus for mycosis fungoides (MF) and Sézary syndrome (SS), which are the main forms of cutaneous T-cell lymphoma (CTCL). But this view is not shared by the
vast majority of the scientific community. Initially, in the early
1990s HTLV-I Tax DNA was reported to be present in 0% to 20% of CTCL
cases, and only the Zucker-Franklin group reported numbers up
to 95%.1
To settle the issue several groups checked their methods, and in 1996 and 1997 a number of papers appeared showing that the number of HTLV-I Tax-positive cases decreased in parallel to increased stringency of the polymerase chain reaction (PCR) conditions and the
numbers of controls for the reagents used.2-7 All these
studies indicated that HTLV-I Tax DNA is not present in MF and SS.
Even in Japan, where HTLV-I is endemic, no HTLV-I tax DNA could be
detected in CTCL cells of MF and SS patients.4 Thus, to
put it bluntly, HTLV-I Tax cannot be the main stimulus of MF or SS, as
it is not present in the malignant or surrounding cells. But one cannot
exclude that another virus (for example, an endogenous retrovirus, or
ERV) is activated in CTCL cells and that these cells contain amplified
DNA sequences that are similar to HTLV-I Tax sequences and proteins
that crossreact with HTLV-I Tax.
Reasons for finding HTLV-I Tax DNA in CTCL are probably inadequate PCR
conditions and misdiagnosis of CTCL. Patients with adult T-cell
leukemia (ATL) often show skin lesions that resemble hypopigmented MF.
Such a misdiagnosis occurred when the HUT78 and HUT102 cell lines were
established.8 Both cell lines were initially described as
SS and MF cell lines, respectively.9 But later it turned
out that the patient from whom the HUT102 cell line had been
derived died from ATL. Further examinations showed that HUT78 is a true
SS cell line, whereas HUT102 is an HTLV-I-producing ATL cell
line.10
Udo Döbbeling
Correspondence: Department of Dermatology, University Hospital
Zurich, Gloriastrasse 31, Zurich, Switzerland
References
1.
Pancake BA, Zucker-Franklin D, Coutavas EE.
The cutaneous T cell lymphoma, mycosis fungoides, is a human T cell lymphotropic virus-associated disease: a study of 50 patients.
J Clin Invest.
1995;95:547-554.
2.
Li G, Vowels BR, 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].
3.
Bazarbachi A, Soriano V, Pawson R, et al.
Mycosis fungoides and Sezary syndrome are not associated with HTLV-I infection: an international study.
Br J Haematol.
1997;98:927-933[CrossRef][Medline]
[Order article via Infotrieve].
4.
Kikuchi A, Nishikawa T, Ikeda Y, Yamaguchi K.
Absence of human T-lymphotropic virus type I in Japanese patients with cutaneous T-cell lymphoma.
Blood.
1997;89:1529-1532[Abstract/Free Full Text].
5.
Wood GS, Schaffer JM, Boni R, et al.
No evidence of HTLV-I proviral integration in lymphoproliferative disorders associated with cutaneous T-cell lymphoma.
Am J Pathol.
1997;150:667-673[Abstract].
6.
Wood GS, Salvekar A, Schaffer J, et al.
Evidence against a role for human T-cell lymphotrophic virus type I (HTLV-I) in the pathogenesis of American cutaneous T-cell lymphoma.
J Invest Dermatol.
1996;107:301-307[CrossRef][Medline]
[Order article via Infotrieve].
7.
Boni R, Davis-Daneshfar A, Burg G, Fuchs D, Wood GS.
No detection of HTLV-I proviral DNA in lesional skin biopsies from Swiss and German patients with cutaneous T-cell lymphoma.
Br J Dermatol.
1996;134:282-284[CrossRef][Medline]
[Order article via Infotrieve].
8.
Bunn PA, Foss FM.
T-cell lymphoma cell lines (HUT102 and HUT78) established at the National Cancer Institute: history and importance to understanding the biology, clinical features, and therapy of cutaneous T-cell lymphomas (CTCL) and adult T-cell leukemia lymphomas (ATLL).
J Cell Biochem.
1996;(suppl 24):12-23.
9.
Gazdar AF, Carney DN, Bunn PA, et al.
Mitogen requirements for the in vitro propagation of cutaneous T-cell lymphomas.
Blood.
1980;55:409-417[Free Full Text].
10.
Poiesz BJ, Ruscetti FW, Mier JW, Woods AM, Gallo RC.
T-cell lines established from human T-lymphocytic neoplasias by direct response to T-cell growth factor.
Proc Natl Acad Sci U S A.
1980;77:6815-6819[Abstract/Free Full Text]
