Stage-Specific Degradation of Cyclin D3 Orchestrates Myelopoiesis and Restrains Myeloproliferative Neoplasm Development.

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. In this study, 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 from D3T283A mice exhibited increased self-renewal and a competitive repopulation advantage in irradiated immunocompromised recipients. Prolonged D3T283A expression drove highly penetrant myeloproliferative neoplasm 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. SIGNIFICANCE: Impaired cyclin D3 degradation disrupts lineage balance, enhances granulocyte-monocyte output, and activates FOXM1/PRMT5-mediated transcriptomic programs driving myeloproliferative neoplasms.