Concise Review: Getting to the Core of Inherited Bone Marrow Failures.
Concise Review: Getting to the Core of Inherited Bone Marrow Failures.
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DOI：
10.1002/stem.2543
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发表时间：
2017-02
期刊：
影响因子：
--
通讯作者：
Lako M
中科院分区：
文献类型：
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作者：
Adam S;Melguizo Sanchis D;El-Kamah G;Samarasinghe S;Alharthi S;Armstrong L;Lako M
骨髓衰竭综合征（BMFS）是一组具有复杂病理生理学的疾病，其特征在于外周血细胞减少和/或骨髓发育不良的常见表型。了解遗传因素有助于BMFS的病理生理学，使致病基因的鉴定和诊断测试的发展。迄今为止，已经鉴定了40多个涉及基因组稳定性维持、DNA修复、核糖体和端粒生物学的基因突变。此外，病理生理学研究提供了一些生物学途径的见解，导致基因型/表型相关性的表征，以及诊断方法和管理策略的发展。骨髓移植技术的最新发展和预处理方案的选择有助于改善移植结果。然而，目前的发病率和死亡率仍然是不可接受的，强调需要在这一领域进行进一步的研究。由于难以完全复制人类突变以及小鼠和人类细胞在端粒长度调节、活性氧物质加工和寿命方面的差异，小鼠研究在很大程度上无法模拟人类疾病表型。诱导多能性的最新进展为疾病发病机制提供了新的见解，并为识别大规模染色体缺失相关疾病中涉及的单倍型不足基因的信号传导途径和功能定位提供了极好的平台。在这篇综述中，我们总结了BMFS领域的知识现状，特别关注遗传形式的建模以及如何最好地利用这些模型来开发靶向治疗。干细胞2017;35：284-298
Bone marrow failure syndromes (BMFS) are a group of disorders with complex pathophysiology characterized by a common phenotype of peripheral cytopenia and/or hypoplastic bone marrow. Understanding genetic factors contributing to the pathophysiology of BMFS has enabled the identification of causative genes and development of diagnostic tests. To date more than 40 mutations in genes involved in maintenance of genomic stability, DNA repair, ribosome and telomere biology have been identified. In addition, pathophysiological studies have provided insights into several biological pathways leading to the characterization of genotype/phenotype correlations as well as the development of diagnostic approaches and management strategies. Recent developments in bone marrow transplant techniques and the choice of conditioning regimens have helped improve transplant outcomes. However, current morbidity and mortality remain unacceptable underlining the need for further research in this area. Studies in mice have largely been unable to mimic disease phenotype in humans due to difficulties in fully replicating the human mutations and the differences between mouse and human cells with regard to telomere length regulation, processing of reactive oxygen species and lifespan. Recent advances in induced pluripotency have provided novel insights into disease pathogenesis and have generated excellent platforms for identifying signaling pathways and functional mapping of haplo‐insufficient genes involved in large‐scale chromosomal deletions–associated disorders. In this review, we have summarized the current state of knowledge in the field of BMFS with specific focus on modeling the inherited forms and how to best utilize these models for the development of targeted therapies. Stem Cells 2017;35:284–298