The kelch protein KLHDC8B guards against mitotic errors, centrosomal amplification, and chromosomal instability

The malignant cell in classical Hodgkin lymphoma (HL) is the binucleated giant Reed-Sternberg cell. Chromosomal instability and mitotic errors may contribute to HL pathogenesis; one potential mitotic regulator is the kelch protein KLHDC8B, which localizes to the midbody, is expressed during mitosis, and is mutated in a subset of familial and sporadic HL. We report that disrupting KLHDC8B function in HeLa cells, B lymphoblasts, and fibroblasts leads to significant increases in multinucleation, multipolar mitoses, failed abscission, asymmetric segregation of daughter nuclei, formation of anucleated daughter cells, centrosomal amplification, and aneuploidy. We recapitulated the major pathologic features of the Reed-Sternberg cell and concluded that KLHDC8B is essential for mitotic integrity and maintenance of chromosomal stability. The significant impact of KLHDC8B implicates the central roles of mitotic regulation and chromosomal segregation in the pathogenesis of HL and provides a novel molecular mechanism for chromosomal instability in HL.