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(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<jats:sup>+<\/jats:sup>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-\u03baB 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.<\/jats:p>","DOI":"10.1038\/s41375-021-01204-6","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T08:03:03Z","timestamp":1615190583000},"page":"968-981","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":251,"title":["Molecular biology of Hodgkin lymphoma"],"prefix":"10.1038","volume":"35","author":[{"given":"Marc A.","family":"Weniger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6691-7191","authenticated-orcid":false,"given":"Ralf","family":"K\u00fcppers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"1204_CR1","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/nrclinonc.2012.91","volume":"9","author":"P Borchmann","year":"2012","unstructured":"Borchmann P, Eichenauer DA, Engert A. 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