Figure 7. Step-wise dysregulation of early cell cycle checkpoints during MGUS and MM evolution (proposed model).

An early event in MM is over-expression of a cyclin D gene as the result of a primary mutation (translocation or hyperdiploidy). Cyclin D over-expression in PCs presumably enables these cells to autonomously overcome the early G₀G₁ checkpoint, contributing to limited clonal PC expansion (MGUS). Over-expression of MYC is one secondary event that may eliminate remaining cell cycle constraints. Significantly, it was recently demonstrated that MYC is directly involved in DNA replication, binding and activating DNA replicative origins and regulating progression of cells into S-phase (Dominguez-Sola et al., 2007). Therefore, we propose that MYC dysregulation is an important progression event between MGUS and MM and mechanistically circumvents cell cycle constraints remaining in cells over-expressing cyclin D by promoting transit into the DNA synthesis S-phase through increased DNA replicative origin activity.