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Receptor for Hyaluronan-Mediated Motility Correlates with Centrosome Abnormalities in Multiple Myeloma and Maintains Mitotic Integrity

Department of Oncology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada

Requests for reprints: Tony Reiman, Department of Medical Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2. Phone: 780-432-8513; Fax: 780-432-8888; E-mail: tonyreim{at}cancerboard.ab.ca.

Elevated expression of receptor for hyaluronan-mediated motility (RHAMM) within ex vivo diagnostic multiple myeloma plasma cells predicts for aggressive disease and patient survival. Here, we investigate the relationship between RHAMM and centrosomal abnormalities within multiple myeloma patient samples. We report that myeloma patient samples contain pervasive structural and numerical centrosomal abnormalities. Structural, but not numerical, centrosomal abnormalities strongly correlate with elevated RHAMM expression. As others have shown that excess pericentriolar material strongly associates with abnormal mitoses, we modeled centrosomal abnormalities with exogenous RHAMM overexpression. RHAMM overexpression in vitro resulted in centrosomal and mitotic defects. To elucidate a mechanism for RHAMM-mediated spindle defects, we further investigated RHAMM mitotic function. RHAMM mitotic localization mirrors that of targeting protein for Xklp2 (TPX2), and RHAMM interacts with the spindle assembly factors dynein and TPX2. Like TPX2, RHAMM expression is up-regulated during mitosis. Moreover, inhibition of function experiments reveals that RHAMM and TPX2 functions converge to maintain spindle integrity after spindle assembly. We postulate that augmentation of RHAMM expression within human cancers, including myeloma, can directly affect centrosomal structure and spindle integrity and potentially modulate apoptotic and cell cycle progression pathways.

Key Words: multiple myeloma • centrosomes • chromosomal instability • 04-01-17 Hematologic, other

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