protein; HL, Hodgkin lymphoma;

The Reed-Sternberg (RS) cell is the driving force behind Hodgkin lym-phoma (HL), a unique malignancy in which the rare RS cell creates an inflam-matory microenvironment that recruits a reactive tumor infiltrate. Well-known oncogenic factors such as nuclear factor kappa B (NFκB) signaling and Epstein-Barr virus infection are linked to HL pathogenesis but do not adequately explain the RS cell’s key pathologic fea-tures of multi-nucleation, abnormalities of centrosome function and number and aneuploidy. Chromosomal instability is also considered a key pathway in the ori-gin of the RS cell, though the molecular mechanisms have largely been a “black box. ” We demonstrated that the mid-body kelch domain protein KLHDC8B protects against mitotic errors, centro-somal amplification and chromosomal instability. Here we discuss how the new findings linking KLHDC8B to mitotic integrity and faithful chromosomal segregation are providing mechanistic explanations for the origin of the RS cell and the molecular pathogenesis of chro-mosomal instability in HL