Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA.
Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA; Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, Illinois, USA.
J Biol Chem. 2024 Aug;300(8):107548. doi: 10.1016/j.jbc.2024.107548. Epub 2024 Jul 9.
Fanconi anemia (FA) is an inherited disorder of DNA repair due to mutation in one of 20+ interrelated genes that repair intrastrand DNA crosslinks and rescue collapsed or stalled replication forks. The most common hematologic abnormality in FA is anemia, but progression to bone marrow failure (BMF), clonal hematopoiesis, or acute myeloid leukemia may also occur. In prior studies, we found that Fanconi DNA repair is required for successful emergency granulopoiesis; the process for rapid neutrophil production during the innate immune response. Specifically, Fancc mice did not develop neutrophilia in response to emergency granulopoiesis stimuli, but instead exhibited apoptosis of bone marrow hematopoietic stem cells and differentiating neutrophils. Repeated emergency granulopoiesis challenges induced BMF in most Fancc mice, with acute myeloid leukemia in survivors. In contrast, we found equivalent neutrophilia during emergency granulopoiesis in FanccTp53 mice and WT mice, without BMF. Since termination of emergency granulopoiesis is triggered by accumulation of bone marrow neutrophils, we hypothesize neutrophilia protects FanccTp53 bone marrow from the stress of a sustained inflammation that is experienced by Fancc mice. In the current work, we found that blocking neutrophil accumulation during emergency granulopoiesis led to BMF in FanccTp53 mice, consistent with this hypothesis. Blocking neutrophilia during emergency granulopoiesis in FanccTp53 mice (but not WT) impaired cell cycle checkpoint activity, also found in Fancc mice. Mechanisms for loss of cell cycle checkpoints during infectious disease challenges may define molecular markers of FA progression, or suggest therapeutic targets for bone marrow protection in this disorder.
范可尼贫血症（FA）是一种由于 20 多个相互关联的基因之一发生突变导致的 DNA 修复遗传性疾病，这些基因可修复链内 DNA 交联并挽救崩溃或停滞的复制叉。FA 最常见的血液学异常是贫血，但也可能进展为骨髓衰竭（BMF）、克隆性造血或急性髓系白血病。在之前的研究中，我们发现 Fanconi DNA 修复对于成功的应急粒细胞生成（在先天免疫反应中快速产生中性粒细胞的过程）是必需的。具体来说，Fancc 小鼠在对紧急粒细胞生成刺激物没有产生中性粒细胞增多，而是表现出骨髓造血干细胞和分化中的中性粒细胞凋亡。大多数 Fancc 小鼠在反复的紧急粒细胞生成挑战中发生了 BMF，幸存者则发生了急性髓系白血病。相比之下，我们在 FanccTp53 小鼠和 WT 小鼠中发现了在应急粒细胞生成期间中性粒细胞增多，没有发生 BMF。由于骨髓中性粒细胞的积累触发了紧急粒细胞生成的终止，我们假设中性粒细胞增多可保护 FanccTp53 骨髓免受 Fancc 小鼠所经历的持续炎症的压力。在目前的工作中，我们发现阻断紧急粒细胞生成期间中性粒细胞的积累会导致 FanccTp53 小鼠发生 BMF，这与这一假说一致。在 FanccTp53 小鼠（而不是 WT 小鼠）中阻断紧急粒细胞生成期间的中性粒细胞增多会损害细胞周期检查点活性，这在 Fancc 小鼠中也有发现。在感染性疾病挑战期间失去细胞周期检查点的机制可能定义了 FA 进展的分子标志物，或者为这种疾病的骨髓保护提供了治疗靶点。
