Fig. 5

Hypothesized mechanism by which CDK4/6 inhibitors increase micronucleus frequency. A Without CDK4/6 inhibitor. The differentiation of erythrocytes is divided into three phases. The first is the proliferation phase, in which cells divide to form hematopoietic stem cells, proerythroblasts, basophilic erythroblasts, polychromatic erythroblasts, and orthochromatic erythroblasts. The second phase is the differentiation phase, in which no further cell division occurs, and chromatin condensation begins. The third phase is the enucleation phase, in which the chromatin is sufficiently condensed and enucleation occurs to form reticulocytes. In the proliferation phase, cell size and nucleus size decrease with division. In the differentiation phase, nucleus size decreases rapidly due to chromatin condensation. Micronuclei occur spontaneously at a certain rate during mitosis, and erythroblasts with micronuclei are removed by apoptosis by the time of the next mitosis. Only the main nucleus is enucleated and micronuclei is not enucleated. B With CDK4/6 inhibitor. Cells in which CDK4/6 is inhibited (yellow lightning mark) stop the cell cycle, exit the proliferation phase, and enter the differentiation phase. Cells enucleate before the cell size decreases and before chromatin becomes sufficiently small and condensed. Therefore, micronuclei are likely to be left in the cell, thus increasing the likelihood of micronuclei forming. In addition, MCV increases because the cells undergo enucleation before they reach a sufficiently small size