Figure 5. Scenarios for the generation of normal CD30⁺ B cells and HRS cells.

(A) The key features of CD30⁺ GC B cells as outlined in the text indicate that CD30⁺ GC B cells represent the positively selected centrocytes (CC) that are preparing to return to the dark zone to become centroblasts (CB) again and undergo an additional round of proliferation and selection. High activity of MYC and E2F and signatures for AP-1 activity are hallmarks of these cells. CD30⁺ EF B cells likely represent reactivated memory B cells that undergo proliferation before they presumably differentiate into plasma cells. It is unclear whether CD30⁺ GC B cells may also directly differentiate into CD30⁺ EF B cells. (B) Scenario for the generation of HRS cells. Genetic features of HRS cells (crippled IgV genes in at least a quarter of cases) strongly indicate that these cells derive from preapoptotic GC B cells that were rescued from apoptosis by some transforming events (e.g., EBV infection in a fraction of cases). The similarities in their gene expression between HRS and CD30⁺ B cells indicate that HRS precursor cells differentiated into the direction of CD30⁺ B cells in the course of their further malignant transformation. Mainly because of the downregulation of GC B cell–specific genes and the strong constitutive NF-κB activity, HRS cells more closely resemble CD30⁺ EF B cells than CD30⁺ GC B cells.