Smith, Dean Edward; (2022) Cellular responses to ionising radiation in multiple myeloma: Influence of D-type cyclin and IgH translocation. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Multiple myeloma (MM) is characterized by over-expression of cyclin D1 or D2, which control G1 phase cell-cycle progression. Proteolytic degradation of cyclin D1 (but not cyclin D2), resulting in G1 arrest, is reported in non-MM cells postDNA damage, affecting DNA repair and survival. The effect of ionizing radiation (IR) on D type cyclin levels and cell-cycle kinetics of MM cells was examined, exploring differences based on D-cyclin expression. It was shown that cyclin D1 is downregulated, whereas cyclin D2 is not, following IR. This did not lead to hypo-phosphorylation of retinoblastoma protein or G1 arrest. Both cyclin D1- and cyclin D2-expressing MM cells arrested in S/G2/M, and did not differ in other cell-cycle proteins or sensitivity to IR. When treated with a CDK4/6 inhibitor, both cyclin D1 and cyclin D2 MM cells arrested in G1 and therefore are subject to physiological regulation at this checkpoint. Immunoprecipitation showed that, despite cyclin D1 degradation following IR, sufficient protein remains bound to CDK4/6 to prevent G1 arrest. Aberrant expression of cyclin D1 driven from the IGH promoter in t(11;14) MM cells maintains progression through G1 to arrest in S/G2/M. Differential expression of D-cyclin does not appear to affect cell cycle response to IR, and is unlikely to underlie differential sensitivity to DNA damage.

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