Cell Of Origin And Evidence Of Disrupted Bcell Transcription Factor Expression

The nature and cell of origin of Hodgkin's disease (HD) has been the subject of debate since the initial description of HD in 1830.1 Not until the mid-1990s was it recognized that the Reed-Sternberg was derived from B-cells and was in most cases a monoclonal proliferation.2-5 These studies utilized single-cell polymerase chain reaction (PCR) from Reed-Sternberg cells to demonstrate monoclonal IGH rearrangements. In the pivotal study, Marafioti and colleagues examined 25 cases of HD by single-cell PCR with amplification of IGH or IGK genes. Twenty-four cases revealed gene rearrangements. Comparison of the PCR products showed that all cases were clonal and 75% of the cases had the capacity for productive rearrangements.5 Furthermore, while the immunoglobulin (Ig) genes were theoretically functional, there was no transcription of Ig genes due to defects in the Ig gene regulatory elements.5

Analysis of the IGH sequences of Reed-Sternberg cells showed a high load of somatic mutations. The presence of these mutations, which occurs in the germinal center in normal B-cells sets the germinal center B-cell as the stage of B-cell maturation for most ReedSternberg cells. This concept is supported by studies of composite Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma in which a common precursor to the two lymphomas can be traced by IGH sequence to a germinal center type B-cell.56 The results of these studies firmly establish HD as HL, a monoclonal B-cell proliferation of cells derived from germinal center or postgerminal center B-cells in the vast majority of cases.

More recent studies provide insight into the mechanisms for a disrupted B-cell transcriptional program.

Oct-2, Bob-1, and Pu.1 are important B-cell transcription factors that have all been shown to be down regulated in classical Hodgkin's lymphoma (cHL).7-10 While they are seen in nodular lymphocyte predominant HL (nLPHL) and other B-cell lymphomas, the absence of these transcription factors serves both as an explanation for lack of Ig transcription and expression in cHL lymphoma as well as a diagnostic marker for this lymphoma. This lack of Ig expression is somewhat problematic since in normal B-cell development, the lack of Ig expression leads to apoptosis. Therefore, other genetic mechanisms must be operative to protect the cell from this fate. One explanation is overexpression of NFkB. This ubiquitous transcription factor has numerous functions in promoting cell survival and proliferation. Recent studies demonstrate the constitutive expression of activated (nuclear) NFkB in HL and that defective IkBa (an inhibitor of NFkB) is a mechanism responsible for this.11-13 With this as background, we proceed with the pathology and classification of HL.

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