Age-associated bone marrow changes include myeloid skewing and mutations that lead to clonal hematopoiesis. Molecular mechanisms for these events are ill defined, but decreased expression of Irf8/Icsbp (interferon regulatory factor 8/interferon consensus sequence binding protein) in aging hematopoietic stem cells may contribute. Irf8 functions as a leukemia suppressor for chronic myeloid leukemia, and young Irf8^−/− mice have neutrophilia with progression to acute myeloid leukemia (AML) with aging. Irf8 is also required to terminate emergency granulopoiesis during the innate immune response, suggesting this may be the physiologic counterpart to leukemia suppression by this transcription factor. Identifying Irf8 effectors may define mediators of both events and thus contributors to age-related bone marrow disorders. In this study, we identified RASSF5 (encoding Nore1) as an Irf8 target gene and investigated the role of Nore1 in hematopoiesis. We found Irf8 activates RASSF5 transcription and increases Nore1a expression during emergency granulopoiesis. Similar to Irf8^−/− mice, we found that young Rassf5^−/− mice had increased neutrophils and progressed to AML with aging. We identified enhanced DNA damage, excess clonal hematopoiesis, and a distinct mutation profile in hematopoietic stem cells from aging Rassf5^−/− mice compared with wildtype. We found sustained emergency granulopoiesis in Rassf5^−/− mice, with repeated episodes accelerating AML, also similar to Irf8^−/− mice. Identifying Nore1a downstream from Irf8 defines a pathway involved in leukemia suppression and the innate immune response and suggests a novel molecular mechanism contributing to age-related clonal myeloid disorders.

与年龄相关的骨髓变化包括骨髓偏斜和导致克隆造血的突变。这些事件的分子机制尚不明确，但衰老造血干细胞中 Irf8/Icsbp（干扰素调节因子 8/干扰素共有序列结合蛋白）表达的降低可能有所贡献。 Irf8 作为慢性粒细胞白血病的白血病抑制因子，年轻的Irf8 ^−/−小鼠患有中性粒细胞增多症，并随着衰老进展为急性粒细胞白血病 (AML)。 Irf8 还需要在先天免疫反应期间终止紧急粒细胞生成，这表明这可能是该转录因子抑制白血病的生理对应物。识别 Irf8 效应子可以定义这两个事件的介质，从而确定与年龄相关的骨髓疾病的促成因素。在本研究中，我们将RASSF5 （编码Nore1）确定为Irf8靶基因，并研究了Nore1在造血中的作用。我们发现 Irf8 在紧急粒细胞生成期间激活RASSF5​​转录并增加 Nore1a 表达。与Irf8 ^−/−小鼠类似，我们发现年轻的Rassf5 ^−/−小鼠中性粒细胞增多，并随着衰老进展为 AML。与野生型相比，我们发现衰老的Rassf5 ^−/−小鼠的造血干细胞中 DNA 损伤增强、克隆造血过多以及独特的突变特征。我们发现Rassf5 ^−/−小鼠有持续的紧急粒细胞生成，反复发作会加速 AML，这也与Irf8 ^−/−小鼠类似。 鉴定 Irf8 下游的 Nore1a 定义了一条参与白血病抑制和先天免疫反应的途径，并提出了一种导致年龄相关克隆性骨髓疾病的新分子机制。