Mutations in a gene encoding a midbody protein in binucleated Reed-Sternberg cells of Hodgkin lymphoma

Abstract

Classical Hodgkin lymphoma (cHL) is a cancer in which malignant "Reed-Sternberg" cells comprise just a fraction of the bulk of the tumor and are characteristically binucleated. We recently identified a novel gene, KLHDC8B, which appears responsible for some familial cases of cHL. KLHDC8B encodes a midbody kelch protein expressed during cytokinesis. Deficiency of KLHDC8B leads to binucleated cells, implicating its involvement in Reed-Sternberg cell formation. Interestingly, other cancer genes, such as BRCA1 and BRCA2, also encode proteins locating to the midbody during cytokinesis, even though their participation in other pathways has received greater attention. Midbody components may be an overlooked source of tumor suppressor genes.

Figure 1

Predicted structure of KLHDC8B, revealing a seven-bladed propeller structure.

Figure 2

Localization of KLHDC8B (green) during mitosis (right cell) and, in particular, at the midbody during cytokinesis (arrow, left cell). Counterstaining of mitotic spindle with α-tubulin (red) and nuclei using DAPI (blue). Shown is a 3D reconstruction of z-stack of confocal imaging of indirect immunofluorescence of HeLa cells.

Figure 3

Binculeated cell formation in HeLa cell expressing dominant negative KLHDC8B, time-lapse photography. Cytokinesis cannot be completed and cleavage furrow regresses.