文章：

GATA2突变等位基因特异性表达与GATA2缺乏综合征中造血干细胞低反应状态相关

GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome

原文发布日期：2025-01-30

DOI: 10.1038/s41408-025-01213-z

类型: Article

开放获取: 是

英文摘要：

GATA2 germline mutations lead to a syndrome characterized by immunodeficiency, vascular disorders and myeloid malignancies. To elucidate how these mutations affect hematopoietic homeostasis, we created a knock-in mouse model expressing the recurrent Gata2 R396Q missense mutation. Employing molecular and functional approaches, we investigated the mutation’s impact on hematopoiesis, revealing significant alterations in the hematopoietic stem and progenitor (HSPC) compartment in young age. These include increased LT-HSC numbers, reduced self-renewal potential, and impaired response to acute inflammatory stimuli. The mature HSPC compartment was primarily affected at the CMP sub-population level. In the mutant LT-HSC population, we identified an aberrant subpopulation strongly expressing CD150, resembling aging, but occurring prematurely. This population showed hyporesponsiveness, accumulated over time, and exhibited allele-specific expression (ASE) favoring the mutated Gata2 allele, also observed in GATA2 mutated patients. Our findings reveal the detrimental impact of a Gata2 recurrent missense mutation on the HSC compartment contributing to its functional decline. Defects in the CMP mature compartment, along with the inflammatory molecular signature, explain the loss of heterogeneity in HPC compartment observed in patients. Finally, our study provides a valuable model that recapitulates the ASE-related pathology observed in GATA2 deficiency, shedding light on the mechanisms contributing to the disease’s natural progression.
 

摘要翻译： 

GATA2种系突变导致一种以免疫缺陷、血管疾病和髓系恶性肿瘤为特征的综合征。为阐明这些突变如何影响造血稳态，我们构建了表达复发性Gata2 R396Q错义突变的敲入小鼠模型。通过分子与功能学方法，我们研究了该突变对造血功能的影响，发现年轻小鼠的造血干细胞与祖细胞（HSPC）区室存在显著改变，包括长期造血干细胞（LT-HSC）数量增加、自我更新能力降低以及对急性炎症刺激的反应受损。成熟HSPC区室主要在共同髓系祖细胞（CMP）亚群层面受到影响。在突变的LT-HSC群体中，我们发现了一个异常高表达CD150的亚群，其表现类似衰老状态，但发生时间显著提前。该亚群呈现低反应性，随时间推移逐渐累积，并表现出偏向突变型Gata2等位基因的等位基因特异性表达（ASE）——这一现象在GATA2突变患者中也得到证实。我们的研究揭示了Gata2复发性错义突变对造血干细胞区室的有害影响，导致其功能衰退。CMP成熟区室的缺陷及炎症分子特征，共同解释了患者体内观察到的造血祖细胞区室异质性丧失现象。最后，本研究提供了一个有价值的模型，能够重现GATA2缺陷患者中观察到的ASE相关病理变化，为阐明疾病自然进展机制提供了新的见解。

原文链接：

GATA2 mutated allele specific expression is associated with a hyporesponsive state of HSC in GATA2 deficiency syndrome