Accumulation of D cyclins during the G1 phase of the cell cycle is a key regulatory step that derepresses the transcriptional program required for DNA replication, facilitating S-phase entry. Among the three D cyclins, cyclin D3 predominates in hematopoietic cells. Accordingly, cyclin D3 mutations are implicated in lymphoid malignancies. Here, we provided evidence demonstrating a critical role for cyclin D3 in myelopoiesis and further demonstrated the stage specific degradation of cyclin D3 dictates normal myelopoiesis. In a knock-in mouse model expressing a degradation-resistant cyclin D3 variant (D3T283A), sustained cyclin D3 protein levels enhanced granulocyte-monocyte differentiation and altered megakaryocyte-erythrocyte outputs, consistent with trends toward microcytic erythrocytes and increased platelet production. This was accompanied by extramedullary hematopoiesis. Splenic hematopoietic stem and progenitor cells (HSPCs) from D3T283A mice exhibited increased self-renewal and a competitive repopulation advantage in irradiated immunocompromised recipients. Prolonged D3T283A expression drove highly penetrant myeloproliferative neoplasm (MPN) development, significantly reducing survival. In contrast, mice with a comparable stabilizing mutation in cyclin D2 (D2T280A), another D cyclin abundant in immune cells, showed no immunophenotypic changes. D3T283A led to upregulation of FOXM1 and PRMT5 dependent transcriptomic programs that played different roles in shaping the immunophenotype, and targeting FOXM1 and PRMT5 suppressed myeloproliferation. Together, these findings highlight a distinct and pivotal role for cyclin D3 in myelopoiesis.
Mucha et al. (2026) studied this question.