PubMed · 11212821
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J Yata. 2000. [Alloimmune disease].. https://pubmed.ncbi.nlm.nih.gov/11212821/
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In classical Hodgkin lymphoma the malignant Hodgkin/Reed-Sternberg (HRS) cells characteristically constitute only a small minority of the tumour load. Their origin has been debated for decades, but on the basis of rearrangement and somatic hypermutations of their immunoglubulin (Ig) genes, HRS cells are now ascribed to the B-cell lineage. Nevertheless, phenotypically HRS cells have lost their B cell identity: they usually lack common B cell-specific surface markers such as CD19 and CD79a as well as Ig gene transcripts. Here we demonstrate that Ig promoters as well as both intronic and 3' enhancer sequences are transcriptionally inactive in HRS cell lines. This inactivity correlates with either reduced levels or even a complete lack of several B cell-specific transcription factors required for their expression: Oct-2, OBF-1, PU.1, E47/E12, PAX-5 and EBF. Moreover, we demonstrate that PU.1 and PAX-5 are significantly down-regulated in HRS cells in pathological specimens from primary tumour tissues. However, forced expression of these transcription factors can activate regulatory sequences of silenced B cell marker genes, and in one instance also transcription from a silenced endogenous locus. Thus, HRS cells are dedifferentiated B cells with global down-regulation of B cell-specific genes.
It is generally accepted that Epstein-Barr virus (EBV) latent genes EBNA-2, EBNA-3A, -3C, EBNA-LP and LMP1 are essential for growth transformation and immortalization of B lymphocytes. Among these genes, LMP1 plays a key role in the survival and dissemination of the infected B cells by inducing anti-apoptotic genes and surface expression of several activation antigens and adhesion molecules. We have previously shown that antisense oligodeoxynucleotides directed to LMP1 mRNA, effectively suppress LMP1 gene expression and substantially reduce B95.8 cell proliferation. In this study, we have used antisense LMP1 oligomers to investigate whether LMP1 suppression might influence the expression of latent EBV genes with oncogenic potential, anti-apoptotic genes, or affect the phenotype of EBV-infected B95.8 cells. Our data show that LMP1 suppression does not affect the transcription of EBNA-2, EBNA-3A, -3B and -3C genes, or that of bcl-2 and mcl-1 anti-apoptotic genes. In contrast, consistent modifications in the expression of CD39, CD54, CD23, CD11 and CD10 molecules were observed in B95.8 cells after treatment with antisense LMP1. Our findings support the possibility for using LMP1 antisense oligomers as therapeutics in EBV-associated tumors.
Normal B lymphocytes as well as malignant B cells extravasate from blood circulation during physiological and pathological processes and require matrix metalloproteinases (MMPs) to facilitate trafficking through the subendothelial basal lamina and the extracellular matrix. We have previously shown that Epstein-Barr virus (EBV)-immortalized B lymphocytes constitutively synthesized low levels of MMP-9 and huge amounts of its preferential inhibitor, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). In the present study, TIMP-1 phenotypic expression was extensively investigated in response to various mediators including interleukins, chemokines, growth factors and tumor promotor, and was compared to MMP-9 synthesis. Results showed a roughly constitutive TIMP-1 expression opposed to an inducible MMP-9 synthesis. Nevertheless, further analysis of TIMP-1 synthesis showed the existence of regulation mechanisms: modulation of intracellular Ca(2+) concentration as well as cation ionophore monensin were demonstrated to influence TIMP-1 production and secretion. The precise pathways implicated in these regulation mechanisms are currently under survey.