Fbw7-dependent cyclin E regulation ensures terminal maturation of bone marrow erythroid cells by restraining oxidative metabolism

Abstract

The mechanisms that coordinate the final mitotic divisions of terminally differentiated bone marrow erythroid cells with components of their structural and functional maturation program remain largely undefined. We previously identified phenotypes resembling those found in early-stage myelodysplastic syndromes, including ineffective erythropoiesis, morphologic dysplasia, and hyper-cellular bone marrow, in a knock-in mouse model in which cyclin E mutations were introduced at its two Cdc4 phosphodegrons (CPDs) to ablate Fbw7-dependent ubiquitination and degradation. Here we have examined the physiologic consequences of cyclin E dysregulation in bone marrow erythroid cells during terminal maturation in vivo. We found cyclin E protein levels in bone marrow erythroid cells are dynamically regulated in a CPD-dependent manner and that disruption of Fbw7-dependent cyclin E regulation impairs terminal erythroid cell maturation at a discrete stage prior to enucleation. At this stage of erythroid cell maturation, CPD phosphorylation of cyclin E regulates both cell cycle arrest and survival. We also found normal regulation of cyclin E restrains mitochondrial reactive oxygen species accumulation and expression of genes that promote mitochondrial biogenesis and oxidative metabolism during terminal erythroid maturation. In the setting of dysregulated cyclin E expression, p53 is activated in bone marrow erythroid cells as part of a DNA damage response-type pathway, which mitigates ineffective erythropoiesis, in contrast to the role of p53 induction in other models of dyserythropoiesis. Finally, cyclin E dysregulation and ROS accumulation induce histone H3 lysine 9 hyper-methylation and disrupt components of the normal terminal erythroid maturation gene expression program. Thus, ubiquitin-proteasome pathway control of G1-to-S-phase progression is intrinsically linked to regulation of metabolism and gene expression in terminally differentiating bone marrow erythroid cells.