Myeloperoxidase (MPO) gene alterations with variable clinical penetrance have been found in hereditary MPO deficiency, but their leukemia association in patients and carriers has not been established. Germline MPO alterations were found to be significantly enriched in myeloid neoplasms: 28 pathogenic/likely pathogenic variants were identified in 100 patients. The most common alterations were c.2031-2 A > C, R569W, M519fs* and Y173C accounting for about half of the cases. While functional experiments showed that the marrow stem cell pool of Mpo^−/− mice was not increased, using competitive repopulation demonstrated that Mpo^−/− grafts gained growth advantage over MPO wild type cells. This finding also correlated with increased clonogenic potential after serial replating in the setting of H₂O₂-induced oxidative stress. Furthermore, we demonstrated that H₂O₂-induced DNA damage and activation of error-prone DNA repair may result in secondary genetic damage potentially predisposing to leukemia leukemic evolution. In conclusion, our study for the first time demonstrates that germline MPO variants may constitute risk alleles for MN evolution.

在遗传性 MPO 缺乏症中发现了具有不同临床外显率的髓过氧化物酶(MPO ) 基因改变，但尚未确定其在患者和携带者中与白血病的关系。发现生殖系MPO改变在骨髓肿瘤中显着富集：在 100 名患者中鉴定出 28 种致病/可能致病变异。最常见的更改是 c.2031-2 A > C、R569W、M519fs* 和 Y173C，约占案例的一半。虽然功能实验表明Mpo ^{- / -}小鼠的骨髓干细胞库没有增加，但使用竞争性再增殖表明Mpo ^{- / -}与 MPO 野生型细胞相比，移植物获得了生长优势。这一发现还与在 H ₂ O ₂诱导的氧化应激环境中连续重新电镀后增加的克隆形成潜力相关。此外，我们证明了 H ₂ O ₂诱导的 DNA 损伤和易出错的 DNA 修复的激活可能导致继发性遗传损伤，从而可能导致白血病白血病演变。总之，我们的研究首次表明生殖系MPO变体可能构成 MN 进化的风险等位基因。