Nore1 inhibits age-associated myeloid lineage skewing and clonal hematopoiesis but facilitates termination of emergency (stress) granulopoiesis.
Nore1 inhibits age-associated myeloid lineage skewing and clonal hematopoiesis but facilitates termination of emergency (stress) granulopoiesis.
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DOI：
10.1016/j.jbc.2023.104867
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发表时间：
2023-07
影响因子：
4.8
通讯作者：
Eklund, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Williams, Olatundun;Hu, Liping;Huang, Weiqi;Patel, Priyam;Bartom, Elizabeth T.;Bei, Ling;Hjort, Elizabeth;Hijiya, Christina;Eklund, Elizabeth A.
年龄相关的骨髓改变包括骨髓歪斜和导致克隆造血的突变。这些事件的分子机制尚不明确，但在衰老的造血干细胞中，Irf8/Icsbp（干扰素调节因子8/干扰素一致序列结合蛋白）的表达减少可能与此有关。Irf8作为慢性髓性白血病的白血病抑制因子，年轻的Irf8 - / -小鼠有嗜中性粒细胞，随着年龄的增长进展为急性髓性白血病（AML）。在先天免疫应答过程中，Irf8也需要终止紧急粒细胞生成，这表明这可能是该转录因子对白血病抑制的生理对应。鉴定Irf8效应物可以确定这两种事件的介质，从而确定与年龄相关的骨髓疾病的因素。在这项研究中，我们确定了RASSF5（编码Nore1）作为Irf8的靶基因，并研究了Nore1在造血中的作用。我们发现Irf8激活RASSF5转录，并在紧急粒细胞形成过程中增加Nore1a的表达。与Irf8−/−小鼠类似，我们发现年轻的Rassf5−/−小鼠中性粒细胞增加，并随着年龄的增长进展为AML。我们发现，与野生型相比，衰老Rassf5 - / -小鼠的DNA损伤增强，克隆造血过剩，造血干细胞突变谱明显。我们在Rassf5 - / -小鼠中发现持续的紧急粒细胞生成，反复发作加速AML，也类似于Irf8 - / -小鼠。在Irf8下游发现Nore1a，确定了一条参与白血病抑制和先天免疫应答的途径，并提出了一种促进年龄相关克隆性髓系疾病的新分子机制。
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.
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