As a result of chromosomal breaks, the translocation of the NFkB2 (lyt-10) gene is found in malignant cells of 5-10% of all CTCL patients (74,75). The NFkB2 (lyt-10) gene codes for a transcription factor which is a member of the NFkB/Rel/IkB gene family comprising at least 10 different genes regulating gene expression (see for review Ref. 76). Proteins of the members of the NFkB and Rel subfamilies occur in the nuclei of cells only after stimulation by an external inducer which can be a growth factor (e.g., IL-1) or a stress signal (e.g., oxygen radicals, hypoxia). The indu-cers activate tyrosine and serine/threonine kinases which in turn activate proteases which process the transcriptionally inactive NFkB1 and NFkB2 gene products p105 and p100 to their active forms p50 and p52 by degradation of the carboxy-ter-minus which retains these proteins in the cytoplasm. The processed p50 and p52 proteins can form heterodimers with members of the Rel subfamily. These heterodimers translocate to the nucleus where they activate the transcription of their target genes. Beside the NFkB/Rel heterodimers, the p50/p50 homodimers and p52/bcl-3 hetero-dimers can also be found in the nuclei of stimulated cells. An alternative NFkB activation pathway is the recruitment of p50/Rel heterodimers from cytoplasmic transcriptionally inactive p50/rel/IkB trimeric complexes by the proteolytic degradation of the IkB component (76).

The observed NFkB2 translocations result in NFkB2 gene products which lack parts of their carboxy-termini which retain them in the cytoplasm. These proteins can translocate to the nucleus where they may disturb the "normal" pattern of gene transcription (77-82).

Electrophoretic mobility shift assays (EMSA) and western blotting demonstrate that other family members of the NFkB/Rel/IkB gene family also are consti-tutively active in the nucleus (own unpublished data). In nucleic extracts from the three CTCL cell lines (HUT78, MyLa and SeAx), p50 (NFkB1), p52 (NFkB2), p65 (RelA), RelB, and bcl-3 could be detected. The truncated NFkB2 protein (79,82) also could be demonstrated in the HUT78 cell line. In the nuclei, this protein was less abundant than the properly processed p52 protein. These proteins bind as p50/p50 homodimers, p50/p65 and p50/RelB heterodimers to an NFkB consensus sequence. P52/Bcl-3 heterodimers may also occur, but probably bind to another sequence. Western blots showed that the p50 and p52 proteins were of correct size and it is therefore unlikely that these proteins derive from translocated genes. The processed p50 and p52 proteins must therefore be the products of a constitutive protease activity that may be triggered by constitutive tyrosine or serine/threonine kinase activities, since the tyrosine kinase inhibitor herbimycin suppresses the DNA binding of NFkB proteins in CTCL cell lines (own unpublished data). This protease activity is also present in the malignant cells of CTCL patients since p50/p50 homodimers are also found in these cells. The appearance of this constitutive protease activity seems to be an early step in the development of cutaneous T-cell lymphoma. This activity has been found in 10 of 11 (91%) patients tested so far. Whether the appearance of gene products of the Rel family in CTCL cell lines is a late step in CTCL tumorigenesis or an adaptation to in vitro cell culture, has to be established.


The proliferation of T-cells in the skin significantly relies on interaction with other cellular and humoral components (83). Clinical as well as histological features suggest that CTCL clones, in most cases, need the presence of epidermal cells to survive, and thus depend on the epidermal cytokine network (84). Paracrine loops between epidermal cells and lymphocytes create a microenvironment which allows the growth of malignant T-cell clones, but suppresses reactive cells like macrophages, natural killer cells or cytotoxic T-cells. In addition, fibrobasts also may be essential micro-environmental components by preventing IL-2-deprived T-cells from going into apoptosis without inducing proliferation due to a selective effect on Bcl-XL expression (85,86). If the conditions are changed and lymphocytes isolated from a skin biopsy are cultured in the presence of IL-2 and IL-4, only the reactive, not tumor-clone derived, cells expand (87), unless the growth of tumor cells is stimulated by immature dendritic cells (88).

Hypothesis for CTCL Lymphomagenesis

For CTCL lymphomagenesis, we propose the following hypothesis. Abnormal but not primarily neoplastic lymphocytes showing genomic instability ("genotraumatic lymphocytes") (89,90) are driven into activation and reactive cell proliferation by antigenic stimulation. The risk of the occurrence of mutations in the susceptible "genotraumatic" cell clone increases with every new cell division. The accumulation of mutations is usually limited by controlling mechanisms leading to cell death in order to prevent cells with chromosomal aberrations from unlimited, neoplastic expansion. Such controlling mechanisms are programmed cell death (apoptosis) which can be blocked by increased bcl-2 protein expression (91) due to bcl-2 gene mutation or translocation.

Normal cells in culture have a limited proliferative capacity of 50-70 cell cycles. Thereafter, they die due to cutting off telomeres which are repetitive base sequences (TTAGGG) at the end of each chromosome, responsible for the maintenance of chromosomal structure and function (92,93). Immortal cells overcome this regulation and proliferate indefinitely by reactivation of telomerase activity, a ribonucleo-

protein complex, which can prevent shortening of the telomeres. Telomerase is believed to be induced upon proliferation and inhibited when cells differentiate. Thus, regulation of telomerase activity may be an important mechanism to limit growth of normal and cancer cells. The enzyme telomerase, present especially in highly replicating cell systems, such as keratinocytes (94) or lymphocytes, shows a significant increase of activity in CTCL (95) and in CTCL cell lines. The unlimited proliferation leads to accumulation of mutations finally resulting in a highly abnormal cell clone which grows independently from external stimuli due to autocrine or paracrine stimulation. In this pathogenetic model, tumor formation results from multiple independent genetic changes accumulated in the same cell and a series of clonal expansions after > 100 doublings, provided a frequency of spontaneous mutations of 10 to the 6.

The transformation from "normal" lymphocytes in preneoplastic stages to highly atypical neoplastic cells in the tumor stage of CTCL is a stepwise process with clear-cut breakpoints in the clinical and histological features as well as immunophe-notypic profile of the skin infiltrates (Fig. 1). Four possible steps in lymphomagenesis of CL can be delineated.

Step One

Chronic activation of lymphocytes with genetic instability leads to the development of preneoplastic lymphoproliferative condition. This step represents a potentially reversible process caused by increased activities of some transcription factors (c-myb, bcl-3, STAT5)—which in turn increase the expression of survival genes (bcl-2, bcl-xL, mcl-1)—and the endogenous production of cell growth factors (IL-15) (64,96-98).

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