Proficient mismatch repair protein expression in Hodgkin and Reed Sternberg cells

Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

“…During the course of our studies two independent laboratories reported a correlation between Ig promoter inactivity and absence of Oct-2 and OBF-1 in HRS cell lines (Theil et al, 2001;Re et al, 2001;Stein et al, 2001). Moreover, in agreement with our findings, they were unable to detect Oct-2 and OBF-1 in the majority of primary HRS cells.…”

“…For technical reasons we were unable to perform conclusive analyses regarding EBF and E47. Regarding Oct-2 we confirm a previous report (Re et al, 2001) that this transcription factor is not expressed in the majority of cases of classical HL (data not shown).…”

“…During the course of our study, two independent laboratories reported that HRS derived cell lines and most primary HRS cells are devoid of the largely B cell restricted transcription factors Oct-2 and OBF-1 that interact with the octamer motif ATGCAAAT present in all promoters and enhancers of Ig genes and of several other B cell-specific genes (Re et al, 2001;Stein et al, 2001;Theil et al, 2001). Since this motif is essential for activity of Ig gene promoters, these authors suggested a causative link between absence of these two transcription factors and Ig gene expression.…”

Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin's lymphoma cells from autonomous Fas-mediated death

“…In the majority of cases HRS cells are believed to derive from GC B cells that have lost the capacity to express functional BCR (1,2,(6)(7)(8). Ordinarily these cells would die by apoptosis, but they are presumably rescued by a transforming event that enables them to evade cell death in the absence of the normal physiological survival signals.…”

“…During the GC reaction, B cells with self-reactive or low-affinity antibody die by Fas (CD95͞APO-1)-mediated apoptosis, whereas cells that express Ig with increased affinity for the corresponding antigen are stimulated to proliferate and exit the GC as memory B cells or plasma cells (3)(4)(5). In contrast, although HRS cells have rearranged Ig genes, they do not express a functional B cell receptor (BCR), either because of crippling mutations in their somatically mutated Ig genes (1,2) or because of the loss of transcription factors important for Ig transcription, namely Oct2 and Bob.1 (6)(7)(8). Thus, a fundamental pathogenetic event in the development of HL is the ability of HRS cells to escape the Fas-mediated apoptosis that would be the normal fate of GC B cells lacking functional BCR expression.…”