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 Blood, 1 February 2008, Vol. 111, No. 3, pp. 1603-1609.
Prepublished online as a Blood First Edition Paper on November 15, 2007; DOI 10.1182/blood-2007-06-097774.

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NEOPLASIA

The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition

Wee J. Chng1, Esteban Braggio1, George Mulligan2, Barbara Bryant2, Ellen Remstein3, Riccardo Valdez4, Ahmet Dogan3, and Rafael Fonseca1

1 Department of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ; 2 Millennium Pharmaceuticals, Cambridge, MA; 3 Department of Pathology, Mayo Clinic, Rochester, MN; and 4 Department of Pathology, Mayo Clinic, Scottsdale, AZ

Centrosome amplification is common in myeloma and may be involved in disease pathogenesis. We have previously derived a gene expression–based centrosome index (CI) that correlated with centrosome amplification and was an independent prognostic factor in a small cohort of heterogeneously treated patients. In this study, we validated the prognostic significance of the CI in 2 large cohorts of patients entered into clinical trials and showed that a high CI is a powerful independent prognostic factor in both newly diagnosed and relapsed patients, whether treated by intensive therapy (total therapy II) or novel agents (bortezomib). Tumors with high CI overexpressed genes coding for proteins involved in cell cycle, proliferation, DNA damage, and G2-M checkpoints, and associated with the centrosome and kinetochore/ microtubules. In particular, aurora kinases are significantly overexpressed in patients with high CI, with concordant increase in protein expression. Human myeloma cell lines with higher CI are more responsive to treatment with a novel aurora kinase inhibitor. Aurora kinase may represent novel therapeutic targets in these patients with very poor prognosis.


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