Induction of Moderate DNA Damage Enhances Megakaryopoiesis and Platelet Production.

Abstract

Megakaryocytes (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 instability on megakaryopoiesis. Poly-ADP ribose polymerase (PARP) inhibitors are chemotherapeutics that result in accumulation of DNA damage and are commonly associated with thrombocytopenia, presumably mediated through platelet progenitors, MKs. To explore PARP inhibitor-induced thrombocytopenia, we treated mice with the PARP inhibitor Niraparib. While high dose Niraparib treatment led to thrombocytopenia, consistent with clinical observations, lower dosage treatment led to a significant increase in bone marrow MKs, MK progenitors, and circulating platelets. This increase was accompanied by elevated DNA damage in both MKs and MK progenitors, as measured by gH2AX accumulation and comet assays. Notably, platelets from Niraparib-treated mice were functionally normal in their response to ADP, TRAP, and collagen. Treatment of mice with low-dose gamma-irradiation similarly led to DNA damage in MKs and resulted in increased MK and platelet counts, suggesting that moderate DNA damage is a common mechanism that enhances megakaryopoiesis and 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.