Centrosome amplification and aneuploidy in bone marrow failure patients

Patients with bone marrow failure are at risk for development of hematopoietic progenitor clones with abnormal numbers of chromosomes (aneuploidy) and leukemia. Numerical centrosome abnormalities or mutations in genes associated with the mitotic spindle checkpoint (BUB1 and MAD2) are two important mechanisms that can induce abnormal mitosis resulting in aneuploid daughter cells. To assess the role of these mechanisms, we used fluorescence in situ hybridization techniques to determine aneuploidy and centrosome copy number and PCR-SSCP to identify gene mutations of BUB1 and MAD2 in marrow cells of 25 patients. No mutations were found in BUB1 or MAD2 genes. However, we found that cells with more than two centrosomes exhibited aneuploidy for three or more chromosomes. We conclude that centrosome amplification may be associated with the development of a clonal population of potentially preleukemic aneuploid cells.