Clinical implication of centrosome amplification and expression of centrosomal functional genes in multiple myeloma

Abstract

BackgroundMultiple myeloma (MM) is a low proliferative tumor of postgerminal center plasma cell (PC). Centrosome amplification (CA) is supposed to be one of the mechanisms leading to chromosomal instability. Also, CA is associated with deregulation of cell cycle, mitosis, DNA repair and proliferation. The aim of our study was to evaluate the prognostic significance and possible role of CA in pathogenesis and analysis of mitotic genes as mitotic disruption markers.Design and methodsA total of 173 patients were evaluated for this study. CD138+ cells were separated by MACS. Immunofluorescent labeling of centrin was used for evaluation of centrosome amplification in PCs. Interphase FISH with cytoplasmic immunoglobulin light chain staining (cIg FISH) and qRT-PCR were performed on PCs.ResultsBased on the immunofluorescent staining results, all patients were divided into two groups: CA positive (38.2%) and CA negative (61.8%). Among the newly diagnosed patients, worse overall survival was indicated in the CA negative group (44/74) in comparison to the CA positive group (30/74) (P = 0.019).Gene expression was significantly down-regulated in the CA positive group in comparison to CA negative in the following genes: AURKB, PLK4, TUBG1 (P < 0.05). Gene expression was significantly down-regulated in newly diagnosed in comparison to relapsed patients in the following genes: AURKA, AURKB, CCNB1, CCNB2, CETN2, HMMR, PLK4, PCNT, and TACC3 (P < 0.05).ConclusionsOur findings indicate better prognosis for CA positive newly diagnosed patients. Considering revealed clinical and gene expression heterogeneity between CA negative and CA positive patients, there is a possibility to characterize centrosome amplification as a notable event in multiple myeloma pathogenesis.

Drug Targeting of Genomic Instability in Multiple Myeloma

“…Dementyeva et al (2010) found CA to be more frequent in B cells from MM patients when compared to those from healthy individuals. They also reported on the prognostic significance of the number of CA abnormalities and on the expression of centrosomal genes which were found to be downregulated in newly diagnosed (ND) patients, compared to relapsed patients (Dementyeva et al, 2013). In their study, ND MM patients with CA had a better prognosis compared to the CA negative group, indicating the clinical significance of centrosome clustering.…”

γ-Tubulin–γ-Tubulin Interactions as the Basis for the Formation of a Meshwork

“…Importantly, γ-tubulin is related to several human diseases. Levels of γ-tubulin are increased in various tumors, and inhibition of the GTPase activity of γ-tubulin in RB1-deficient tumor cells impedes tumor growth [ 24 , 25 , 56 , 77 , 78 , 79 , 80 , 81 , 82 ]. Mutations in the TUBG genes have also been found to cause brain malformations [ 54 , 83 ].…”

The therapeutic potential of cell cycle targeting in multiple myeloma

“…The previously used centrosome index (based on gene expression) demonstrates an association with poor prognosis in myeloma patients. In contrast, a more recent study (using immunofluorescent staining) indicates a better prognosis in newly diagnosed myeloma patients who are centrosome amplification positive [ 82 ]. The second mitotic kinase family are the polo-like kinases (1, 2, 3, 4 and 5).…”