Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma

Abstract

Hodgkin's and Reed/Sternberg (HRS) cells, the tumour cells in classical Hodgkin's lymphoma (HL), represent transformed B cells in nearly all cases. The detection of destructive somatic mutations in the rearranged immunoglobulin (Ig) genes of HRS cells in classical HL indicated that they originate from preapoptotic germinal centre (GC) B cells that lost the capacity to express a highaffinity B-cell receptor (BCR). Several aberrantly activated signalling pathways and transcription factors have been identified that contribute to the rescue of HRS cells from apoptosis. Among the deregulated signalling pathways, activation of multiple receptor tyrosine kinases in HRS cells appears to be a specific feature of HL. In about 40% of cases of classical HL the HRS cells are infected by Epstein-Barr virus (EBV), indicating an important role of EBV in HL pathogenesis. Interestingly, nearly all cases of HL with destructive Ig gene mutations eliminating BCR expression (e.g. nonsense mutations) are EBV-positive, suggesting that EBV-encoded genes have a particular function to prevent apoptosis of HRS-cell precursors that acquired such crippling mutations. This idea is further supported by the recent demonstration that isolated human GC B cells harbouring crippled Ig genes can be rescued by EBV from cell death, giving rise to lymphoblastoid cell lines. The molecular analysis of composite Hodgkin's and nonHodgkin's lymphomas indicated that many cases develop from a common GC B-cell precursor in a multistep transformation process with both shared and distinct oncogenic events. 2-6 Nearly all cases of classical and lymphocyte-predominance HL carry somatically mutated V genes, suggesting an origin from (post) germinal centre (GC) B cells, as somatic hypermutation of Ig V genes specifically takes place in GC B cells.7 In lymphocyte-predominance HL, the detection of intraclonal V gene diversity and several phenotypic features suggest an origin of the L&H cells from mutating and selected GC B cells. 2,4,5 In classical HL, crippling mutations that destroyed the coding capacity of originally functional rearrangements were detected in about a quarter of cases.3,8 Such obviously crippling mutations happen in mutating GC B cells, but represent only a small fraction of all disadvantagous mutations that normally result in apoptosis of the respective GC B cells. In the GC, there is a stringent selection for B cells acquiring affinity-increasing mutations, so also many GC B cells that still express a B-cell receptor (BCR) but which fails to bind to the cognate antigen with improved affinity will undergo apoptosis.9,10 Thus, we speculated that the vast majority of HRS cells in classical HL are derived from preapoptotic GC B cells. 3 In rare cases (about 2%) HRS cells originate from T cells. 11,12 Although HRS cells are usually transformed B cells, global gene expression analysis of HRS cell lines using microarrays revealed that the HRS cells have lost the expression of most B-cell markers to an extent that is unique among B-cell lymphomas. 13 As t...

Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma

“…Given the different cellular origin of ALCL and cHL, it is striking that the downregulation of multiple markers of the respective cells of origin in these two CD30 þ lymphoid malignancies results in a related, 'hyperactivated' gene expression programme. 13 Genes showing a consistently and at least several-fold different expression in ALK À ALCL and cHL may become novel markers for differential diagnosis (Supplementary Table S4). …”

“…The neoplastic Hodgkin and Reed-Sternberg (HRS) cells of cHL also express CD30, are commonly derived from germinal centre B cells, but lack expression of most B-cell markers and may express T-cell molecules. 13,14 Besides PAX5/BSAP, which is expressed in most cHL, but not in ALCL, no phenotypic marker has been identified to unambiguously distinguish cHL, especially tumour cell-rich cases, from ALK À ALCL. 7 We compared gene expression profiles of laser-microdissected neoplastic cells of ALK þ , ALK À and cALCL with each other and with expression profiles of cHL and of flow-cytometrically isolated cells of the main subsets of normal T and NK cells to gain insight into the pathogenesis and relationship of these lymphomas.…”

HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

“…The classic Reed-Sternberg cells of HL represent postgerminal center B cells, which contain nonfunctional immunoglobulin genes (26,27). In EBV-positive HL, these abnormal cells are thought to have been rescued from apoptosis in germinal centers by the expression of EBV latent membrane proteins 1 and 2, which provide crucial survival signals (28). We postulate that the HLA class I markers D6S510 and D6S265 predispose to EBV-associated HL by inducing a suboptimal T cell immune response to the virus during IM, which in turn would result in poor virus clearance, allowing a high level of virus persistence in B cells.…”

Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo

“…3 Several lines of evidence indicate that the infiltrating cells are necessary for the survival of the HL cells by providing growth and survival signals, and protection from NK cells. 3,4 MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level by base-pairing to target mRNAs and promoting transcript instability and/or translational repression. 5 Mature miRNAs derive from long hairpin precursors that are sequentially processed by the RNase-III-type enzymes DROSHA and DICER1, respectively.…”