> top > docs > PMC:2195754 > div:1

PMC:2195754 (1) JSONTXT < >

Hodgkin's lymphoma (HL) is the most common type of malignant lymphoma in the Western world. It is distinguished from other tumors by a peculiar histological presentation: the giant, often bi- or multinucleated malignant cells, termed Hodgkin and Reed-Sternberg (H/RS) cells, constitute <1% of all cells in the tumor tissue. They are surrounded by an excess of inflammatory cells, e.g., lymphocytes, macrophages, and eosinophils, which are believed to be drawn into the tumor by a deregulated immune reaction precipitated by the H/RS cells 1.
Investigations into the molecular biology of H/RS cells are hampered by their scarcity in the tumor tissue. A detailed analysis of their origin was made possible by the combination of micromanipulation of H/RS cells from frozen tissue sections with PCR amplification of genes from single cells 2 3. Amplification of V(D)J gene rearrangements on the loci coding for IgH and IgL chains revealed the clonal nature of H/RS cells and their derivation from mature B cells. Deleterious (“crippling”) somatic mutations found in some of these rearrangements indicated that the B cell precursors of H/RS cells resided within the germinal center, and have acquired the capacity to survive loss of B cell receptor expression, an event that would otherwise invariably lead to death by apoptosis of a germinal center B cell 4. Consequently, resistance to apoptosis must play a crucial role in the pathogenesis of the malignant cells.
Despite the impressive progress made in the treatment of HL, the pathogenesis of the tumor and in particular the molecular events leading to transformation of the malignant cells remain to be elucidated. Even though studies on HL-derived tissue or cell lines suggested that p53 mutations or bcl-2 translocations might play a role in the pathogenesis of HL, neither of these ideas could be validated when primary H/RS cells were investigated 5 6. In some cases of HL, the H/RS cells carry EBV and express EBV-encoded proteins such as the oncogenic latent membrane protein 1 (LMP-1 7). However, most cases of HL prevalent among young adults in Western countries are EBV-negative. The distinct epidemiology of these cases has led to various speculations about their pathogenesis, but no other virus or recurrent transforming genetic defect has been identified to date.
Studies in several HL-derived cell lines identified constitutive nuclear factor (NF)-κB activity as their characteristic feature 8, suggesting a role for NF-κB in the pathogenesis of HL. In line with this idea, inhibition of NF-κB activity in some of these cell lines led to increased susceptibility to apoptosis and impaired tumorigenicity in nude mice 9. NF-κB activity is mediated by the Rel/NF-κB family of transcription factors, members of which are expressed in virtually all mammalian cells. In most cells, NF-κB is retained in an inactive form in the cytoplasm by binding to members of the IκB family of proteins (for a review, see reference 10). A variety of stimuli leads to the degradation of IκBs, which allows nuclear translocation of NF-κB and target gene activation. Most inducible NF-κB responses in the cell are mediated by the classical NF-κB heterodimer p50/p65 and are of a transient nature, an effect mainly due to the rapid resynthesis of IκBα, the prototypic member of the IκB family. Target genes activated by NF-κB include factors involved in apoptosis resistance, cell activation, and proliferation, as well as cyto- and chemokines involved in immunoregulation 10 11. In fact, NF-κB has been likened to a master switch of immune responses, and accumulating evidence indicates in addition a pivotal role of NF-κB in several pathways of malignant transformation. In lymphoid malignancies, for example, NF-κB deregulation may occur due to chromosomal translocations involving the nfkb2 or bcl3 loci 11 12.
In view of this, the demonstration that constitutive activity of p65 is also a characteristic feature of the H/RS cells in primary cases of HL 9 is highly relevant for the pathogenesis of the tumor. In EBV-positive cases, this NF-κB activity may be caused by the expression of the viral oncogene LMP-1 on the H/RS cells. An intriguing alternative cause of constitutive NF-κB activity has been proposed on the basis of data from two HL-derived cell lines, which show defects in the expression of IκBα protein 13 due to mutations in the IκBα gene 14. However, these cell lines have been established from treated and relapsed patients at late stages of the disease 15, and it is unclear whether they are indeed derived from the rare H/RS cells. Likewise, a mutant IκBα fragment could be amplified from a minute fraction of a partially purified H/RS cell population from a relapsed case of HL 14. Again, it is unclear whether the mutation is derived from the malignant cells. Even if this were the case, it is stated by the authors that this mutation cannot be present in all H/RS cells 14; its relevance for the NF-κB activity in the H/RS cell clone is thus doubtful. Therefore, it is an open question whether IκBα defects play any role in the pathogenetic process that leads to HL.
For many human malignancies, insight into the mechanisms of tumorigenesis has come from the recurrent detection of genetic defects that are common to all cells of the malignant clone and can already be found in primary tumors (rather than sporadic mutations scattered in the tumor that may arise due to its high mutability or upon treatment). It is the clonal nature of mutations that implicates their involvement in the process of malignant transformation—a central criterion for the identification of an oncogene or tumor suppressor gene. In this study, we have analyzed the role of IκBα defects in HL on the basis of this concept.

projects that include this document

Unselected / annnotation Selected / annnotation
Biotea (0)