Year: 2025
Type: preprint
Abstract: A common side effect of poly-ADP ribose polymerase (PARP) inhibitors is low platelet counts, or thrombocytopenia, presumably mediated through platelet progenitors, megakaryocytes (MKs). MKs are large, hematopoietic cells with a polyploid, multi-lobulated nucleus. While DNA replication in MKs (endomitosis) is well studied, limited investigations have examined the impact of DNA damage and repair inhibition on megakaryopoiesis. To explore PARP inhibitor-induced thrombocytopenia, we treated mice with PARP inhibitors (niraparib and olaparib), which are approved for the treatment of solid tumors. While high-dose niraparib treatment led to thrombocytopenia, consistent with clinical observations, treatment at a lower dosage led to a significant, >1.5-fold increase in both the number of bone marrow MKs and circulating platelets. This increase was accompanied by elevated DNA damage in both MKs and MK progenitors, as measured by both γH2AX accumulation and comet assays of MKs. Notably, platelets from niraparib-treated mice were functionally normal in their response to ADP, TRAP, and collagen. Gamma-irradiation treatment similarly increased MK and platelet counts in mice, suggesting that moderate DNA damage enhances megakaryopoiesis and increases platelet counts. These data reveal a previously unknown relationship between MKs and DNA damage and present a novel target for triggering enhanced platelet production in vivo.
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, American Cancer Society, American Heart Association, Washington University in St. Louis, CSL Behring, Alvin J. Siteman Cancer Center, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1280063934, Unraveling Fatty Acid-driven Mechanisms of Platelet Hyper-Activation in Obesity, G2574089533, G3987444586, The Role of CCL5 in Hematopoietic Stem Cell Activation and Skewing, Elucidating the role of fatty acids uptake in thrombopoiesis during diet-induce obesity, An unexplored role for platelets in driving clonal hematopoiesis-related cardiovascular disease, Mechanisms and relevance of miRNA decay during hematopoietic development, G8335351906, G9000065875, G9000077976, G9000234901, Uncovering Novel Regulatory Pathways and Functions of the Telomerase RNA Component in the Hematopoietic System, The Centrosome as a master controller of platelet production., Telomere dysfunction and telomerase reactivation in the etiology and progression of liver cancer
OpenAlex ID: W4410320839