Centrosomal Disruption As Early Event in Myeloma Development

Multiple myeloma (MM) is a malignancy of differentiated B-lymphocytes characterized by accumulation of clonal plasma cells (PCs) in the bone marrow. Genome of malignant PCs is extremely unstable and characterized by complex combination of structural and numerical abnormalities. The basis of genomic instability underlying MM is still unclear. Centrosome amplification (CA) is present in about a third of MM cases and may represent a mechanism leading to genomic instability in myeloma. We have previously shown that CA is present in pre-plasma cells stages of B-cell development.

The objective of our study was to evaluate changes in expression of chosen key genes involved in centrosome duplication process in both B and PCs, including their possible changes during MM progression.

In total, 56 patients were evaluated for this study. Patients' characteristics were as follows: males/females 38/37, median age 69 years (range 43–83 years). Newly diagnosed (27/56) and relapsed (29/56) patients were included in this study; most of them had advanced stage of MM (DS III n=48; ISS II/III n=45). qRT-PCR (51 PCs and 32 B cell samples) was performed on a chosen set of mitotic genes, according to their role in normal centrosome duplication process.

Expression of genes involving in centrosome duplication process was studied in B cells of MM patients and healthy donors. Group of MM patients showed significant increase in relative quantification coefficient R in the following genes: AURKA, AURKB, CCNB1, CCNB2, HMMR, PLK4, TACC3 and TUBG1. It is notable that TUBG1 was approximately 330-times overexpressed in MM B cells vs healthy donors.

Expression of studied genes was significantly different in B and PCs populations of MM patients: AURKB and TACC3 were upregulated in B cells while CENT2 and TUBG1 were upregulated in PCs.

Analyses of gene expression in newly diagnosed and relapsed patients showed significant changes of the following genes: AURKA and TACC3 were 2-times upregulated in PCs of relapsed patients; no differences were detected in population of B cells.

Considering revealed changes in B cells of myeloma patients, we suspect early damage in cell-cycle regulating mechanism. This hypothesis correlates with our previous findings of CA in MM B cells. We anticipate that dynamic accumulation of showed changes plays a role in final transformation of malignant PCs. We assume that centrosomal disruption likely contributes to accumulation of genomic abnormalities in tumor cells during MM progression which can be proven in future long-term study.

This study was supported by grants NT11154, NS10207, MSM0021622434

No relevant conflicts of interest to declare.