Wu Junying, Liu Jinqin, Chen Jia, Yang Lin, Li Fuhui, Qin Tiejun, Xu Zefeng, Liu Jing, Zhou Jiaxi, Shi Lihong, Li Bing, Xiao Zhijian
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
Exp Hematol Oncol. 2025 May 14;14(1):71. doi: 10.1186/s40164-025-00664-1.
Over 90% of patients with myelodysplastic syndromes/neoplasms (MDS) exhibit anemia at diagnosis, primarily due to ineffective erythropoiesis. This is characterized by abnormal proliferation and differentiation of erythroid cells influenced by signaling pathways including heme synthesis, ferroptosis, senescence and apoptosis. Despite widespread anemia, the specific mechanisms and pathway alterations at different disease stages are not well understood. This study employed the NUP98-HOXD13 (NHD13) transgenic mouse model, which mimicked the erythroid changes observed in MDS patients, to explore these dynamic pathway changes during disease progression. Based on the severity of anemia and changes in mean corpuscular volume (MCV), four time points were selected: 6 weeks (non-anemic), 12 weeks (mild anemia), 16 weeks (obvious anemia) and 20 weeks (severe macrocytic anemia). The findings indicated that a reduction in erythroid-committed progenitors and impaired erythroid maturation were linked to ineffective erythropoiesis. As the disease progressed, signaling pathways dynamically changed. Heme metabolism and ferroptosis pathways were significantly upregulated in the pre-disease and early disease stages, while senescence and cell cycle pathways were activated in the early stage. The prominent roles of apoptosis, pyroptosis and inflammasome signaling pathways were observed in the late stage. Notably, changes in Gpx4 and Ncoa4 expression, along with transmission electron microscopy analysis, suggested that ferroptosis played a critical role in the early stage of the disease. To our knowledge, this is the first report of the signaling pathway dynamics associated with ineffective erythropoiesis during the pathogenesis and progression of MDS, highlighting potential targets for therapeutic intervention at various stages of the disease.
超过90%的骨髓增生异常综合征/肿瘤（MDS）患者在诊断时表现出贫血，主要原因是无效造血。其特征是红系细胞的异常增殖和分化，这受到包括血红素合成、铁死亡、衰老和凋亡在内的信号通路影响。尽管贫血普遍存在，但不同疾病阶段的具体机制和通路改变尚不清楚。本研究采用NUP98-HOXD13（NHD13）转基因小鼠模型，该模型模拟了MDS患者中观察到的红系变化，以探索疾病进展过程中的这些动态通路变化。根据贫血的严重程度和平均红细胞体积（MCV）的变化，选择了四个时间点：6周（非贫血）、12周（轻度贫血）、16周（明显贫血）和20周（严重大细胞性贫血）。研究结果表明，红系定向祖细胞减少和红系成熟受损与无效造血有关。随着疾病进展，信号通路动态变化。血红素代谢和铁死亡通路在疾病前期和早期阶段显著上调，而衰老和细胞周期通路在早期被激活。在后期观察到凋亡、焦亡和炎性小体信号通路的突出作用。值得注意的是，Gpx4和Ncoa4表达的变化以及透射电子显微镜分析表明，铁死亡在疾病早期起关键作用。据我们所知，这是第一份关于MDS发病机制和进展过程中与无效造血相关的信号通路动态变化的报告，突出了疾病各个阶段治疗干预的潜在靶点。
