Give megs a break: minor DNA stress, platelets in excess

In this issue of Blood Advances, Camacho et al 1 report that moderate DNA damage enhances megakaryopoiesis and platelet production in mice, providing the first evidence that direct DNA damage can influence megakaryocyte biology.To induce DNA damage, Camacho et al relied on niraparib, an US Food and Drug Administrationapproved poly (ADP-ribose) polymerase (PARP)1/2 inhibitor used to treat ovarian, fallopian tube, and primary peritoneal cancers.Niraparib prevents PARP-dependent recruitment of DNA repair effectors, thereby promoting the accumulation of DNA double-strand breaks. 2 In their study, the authors began by comparing the effects of high (50 mg/kg) and low (25 mg/kg) intraperitoneal doses of niraparib in mice.After 1 week of treatment, mice that received high doses of niraparib developed severe anemia and thrombocytopenia, an observation that mimics the adverse effects reported in some patients. 3Interestingly, low-dose treatment also led to progressive anemia, but this time resulted in mild thrombocytosis.This result was confirmed using another structurally unrelated PARP1/2 inhibitor and was reversible, with no effect on downstream platelet functions.To understand how low doses of niraparib increased platelet counts, Camacho et al performed a detailed analysis of the hematopoietic tree in the bone marrow of treated mice using flow cytometry.This analysis revealed a significant expansion in the number of long-term hematopoietic stem cells (HSC), multipotent progenitor 2 (MPP), megakarycotytic progenitors (MkPs), and megakaryocytes.This expansion was accompanied by clear evidence of DNA damage, as shown by comet assays and the accumulation of phosphorylated H2Ax across most analyzed populations.To assess whether these changes reflected PARP1/2-specific effects or represented a general response to DNA damage, the authors exposed cells to low-dose ionizing radiation (<200 cGy).Similar results were obtained, indicating that DNA damage, rather than PARP-specific inhibition, was the underlying cause.