Exploring the role of cyclin D1 in the pathogenesis of multiple myeloma beyond cell-cycle regulation

ABSTRACT: Background: Several studies have demonstrated that cyclins D could be a unifying event in multiple myeloma (MM), despite its great genomic heterogeneity. Cyclins D are primarily known for their role in cell proliferation, yet MM is not typically considered a proliferative disease. This paradox led us to hypothesize that cyclins D might have additional roles in the pathogenesis of MM beyond cell-cycle regulation. Methods: Basal levels of cyclins D were quantified by RT-qPCR and capillary electrophoresis nanoimmunoassay (CNIA) in nine MM cell lines. CCND1 and CCND2 were ectopically overexpressed in the MM cells lacking them. Changes were analyzed by transcriptome arrays and multidimensional flow cytometry. We validated some of the findings observed in vitro in newly diagnosed MM patients. Results: Cyclin D proteins were predominantly localized in the cytoplasm, where their expression was mutually exclusive. Ectopic overexpression of cyclin D1 or D2 did not affect cell proliferation in most cell lines. Transcriptome analysis revealed that cyclin D1 overexpression influenced the adhesion pathway, significantly upregulating genes such as ZO-1 and FLNA. In addition, cells with ectopic cyclin D1 overexpression had an altered actin cytoskeleton with reduced attachment to certain matrices. Immunophenotypic changes, such as an increase in CD56-negative cells were also observed after cyclin D1 overexpression. This finding was validated in a set of 49 MM patients, where 73% of those with high levels of cyclin D1 expression had CD56-negative cells, while only 11% with low levels were CD56-negative (p<0.001). Consistent with these observations, patients with high cyclin D1 levels had significantly more circulating tumor cells (CTCs) than those not expressing cyclins D (p<0.001). Conclusions: Our study revealed previously undescribed functions of cyclin D1 in the pathogenesis of MM, associated particularly with cell adhesion and morphology, independent of their canonical function in cell-cycle control. These findings were supported by the association between cyclin D1 overexpression and increased levels of CTCs. Both findings suggest roles for cyclin D1 in determining cell metastatic capacity, and thereby in MM dissemination and extramedullary disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277542 | GEO | 2025/12/04

REPOSITORIES: GEO