Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-Kras^G12D × Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-Kras^G12D) were treated with N^α-methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H₂ receptors. M-Kras^G12D mice developed myeloid leukemia comprising mature CD11b⁺Gr1⁺ myeloid cells that produced NOX2-derived ROS. Treatment of M-Kras^G12D mice with NMH delayed the development of myeloproliferative disease and prolonged survival. In addition, NMH-treated M-Kras^G12D mice showed reduction of intracellular ROS along with reduced DNA oxidation and reduced occurence of double-stranded DNA breaks in myeloid cells. The in vivo expansion of leukemia was markedly reduced in triple transgenic mice where KRAS was expressed in hematopoietic cells of animals with genetic NOX2 deficiency (Nox2^-/- × LSL-Kras^G12D × Mx1-Cre). Treatment with NMH did not alter in vivo expansion of leukemia in these NOX2-deficient transgenic mice. We propose that NOX2-derived ROS may contribute to the progression of KRAS-induced leukemia and that strategies to target NOX2 merit further evaluation in RAS-mutated hematopoietic cancer.

中文翻译：

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在鼠KRAS诱导的骨髓增生性疾病中，NOX2抑制作用可降低氧化应激并延长其生存期。

导致组成性RAS激活的突变有助于髓样白血病的发生。髓样细胞中的RAS突变伴随着活性氧（ROS）的过量形成，但是ROS的来源及其在白血病的发生和发展中的作用尚未明确。为了确定NOX2衍生ROS在RAS驱动白血病作用，双转基因LSL-Kras的^G12D 表达在造血细胞中致癌KRAS（M-的Kras×的Mx1 Cre重组小鼠^G12D）分别用N ^α -甲基-组胺（NMH）通过针对组胺H ₂受体的激动剂活性，靶向白血病细胞中NOX2衍生的ROS的产生。M-Kras ^G12D小鼠发生了包含成熟CD11b的骨髓性白血病⁺ Gr1 ⁺产生NOX2衍生的ROS的髓样细胞。用NMH治疗M-Kras ^G12D小鼠延迟了骨髓增生性疾病的发展并延长了生存期。此外，经NMH处理的M-Kras ^G12D小鼠显示出细胞内ROS的减少以及DNA氧化的减少和骨髓细胞中双链DNA断裂的发生的减少。在三重转基因小鼠中，白血病的体内扩增显着减少，其中在具有遗传性NOX2缺乏症的动物（Nox2 ^-/-  ×LSL-Kras ^G12D）的造血细胞中表达了KRAS ×Mx1-Cre）。在这些NOX2缺陷型转基因小鼠中，用NMH处理不会改变白血病的体内扩增。我们建议，NOX2衍生的ROS可能有助于KRAS诱导的白血病的进展，靶向NOX2的策略值得在RAS突变的造血系统癌症中进一步评估。