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 Blood, 24 September 2009, Vol. 114, No. 13, pp. 2699-2708.
Prepublished online as a Blood First Edition Paper on August 3, 2009; DOI 10.1182/blood-2008-12-194290.

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LYMPHOID NEOPLASIA

Aurora kinase A is a target of Wnt/β-catenin involved in multiple myeloma disease progression

Jui Dutta-Simmons1, Yunyu Zhang1, Gullu Gorgun1,2, Moshe Gatt1, Mala Mani1, Teru Hideshima1,2, Kohichi Takada1, Nicole E. Carlson1, Daniel E. Carrasco1, Yu-Tzu Tai1,2, Noopur Raje1,2, Anthony G. Letai1, Kenneth C. Anderson1,2, and Daniel R. Carrasco1,3

1 Department of Medical Oncology and 2 Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and 3 Department of Pathology, Brigham & Women's Hospital, Boston, MA

Multiple myeloma (MM) is a cancer of plasma cells with complex molecular characteristics that evolves from monoclonal gammopathy of undetermined significance, a highly prevalent premalignant condition. MM is the second most frequent hematologic cancer in the United States, and it remains incurable, thereby highlighting the need for new therapeutic approaches, particularly those targeting common molecular pathways involved in disease progression and maintenance, shared across different MM subtypes. Here we report that Wnt/β-catenin is one such pathway. We document the involvement of β-catenin in cell-cycle regulation, proliferation, and invasion contributing to enhanced proliferative and metastatic properties of MM. The pleiotropic effects of β-catenin in MM correlate with its transcriptional function, and we demonstrate regulation of a novel target gene, Aurora kinase A, implicating β-catenin in G2/M regulation. β-catenin and Aurora kinase A are present in most MM but not in normal plasma cells and are expressed in a pattern that parallels progression from monoclonal gammopathy of undetermined significance to MM. Our data provide evidence for a novel functional link between β-catenin and Aurora kinase A, underscoring a critical role of these pathways in MM disease progression.


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