Abstract
Classical Hodgkin lymphoma (cHL) is unique among lymphoid malignancies in several key biological features. (i) The Hodgkin and Reed-Sternberg (HRS) tumor cells are rare among an extensive and complex microenvironment. (ii) They derive from B cells, but have largely lost the B-cell typical gene expression program. (iii) Their specific origin appears to be pre-apoptotic germinal center (GC) B cells. (iv) They consistently develop bi- or multinucleated Reed-Sternberg cells from mononuclear Hodgkin cells. (v) They show constitutive activation of numerous signaling pathways. Recent studies have begun to uncover the basis of these specific features of cHL: HRS cells actively orchestrate their complex microenvironment and attract many distinct subsets of immune cells into the affected tissues, to support their survival and proliferation, and to create an immunosuppressive environment. Reed-Sternberg cells are generated by incomplete cytokinesis and refusion of Hodgkin cells. Epstein-Barr virus (EBV) plays a major role in the rescue of crippled GC B cells from apoptosis and hence is a main player in early steps of lymphomagenesis of EBV+ cHL cases. The analysis of the landscape of genetic lesions in HRS cells so far did not reveal any highly recurrent HRS cell-specific lesions, but major roles of genetic lesions in members of the NF-κB and JAK/STAT pathways and of factors of immune evasion. It is perhaps the combination of the genetic lesions and the peculiar cellular origin of HRS cells that are disease defining. A combination of such genetic lesions and multiple cellular interactions with cells in the microenvironment causes the constitutive activation of many signaling pathways, often interacting in complex fashions. In nodular lymphocyte predominant Hodgkin lymphoma, the GC B cell-derived tumor cells have largely retained their typical GC B-cell expression program and follicular microenvironment. For IgD-positive cases, bacterial antigen triggering has recently been implicated in early stages of its pathogenesis.
Highlights
Hodgkin lymphoma (HL) is one of the most frequent lymphomas in the western world, with an incidence of about 3 new cases per 100,000 individuals per year
In light of the various unique and peculiar features of the biology of classical HL (cHL), the question arises whether there is a link between these characteristics of the disease
B cells are stringently selected for expression of a high affinity B-cell receptor (BCR) and cognate interaction with Th cells, one can imagine a scenario in which crippled germinal center (GC) B cells are under strong selective pressure to escape the B-cell gene expression program and the pressure to execute apoptosis
Summary
Hodgkin lymphoma (HL) is one of the most frequent lymphomas in the western world, with an incidence of about 3 new cases per 100,000 individuals per year. The sequence of events during malignant transformation of pre-apoptotic GC B cells toward HRS cells is poorly understood, but escape from programmed cell death seems to be an early and essential event In this regard, it is an intriguing observation that all cases with crippling mutations that prevent expression of a BCR were found to be Epstein-Barr virus (EBV) positive [17]. A main finding from numerous studies is that mutations in members of the NF-κB pathway are a main feature of HRS cells (Table 1) This includes gains and amplifications of the genes encoding the NF-κB factor REL, the kinase MAP3K14 ( known as NIK), and BCL3 [34–38].
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