Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin
Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin
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DOI：
10.1182/blood-2017-02-768036
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发表时间：
2017-08-17
期刊：
影响因子：
20.3
通讯作者：
Shimamura, Akiko
中科院分区：
文献类型：
--
作者：
Seo, Aaron;Ben-Harosh, Miri;Shimamura, Akiko
我们报告了3个不相关家庭中的5名严重血小板减少症患者进展为三岁期骨髓衰竭（BMF）。其中4名儿童接受了造血干细胞移植，即使在不同供者的反复移植后，仍表现出移植物功能差和持续严重的细胞减少。外显子组和靶向测序鉴定出编码血小板生成素（THPO）的基因突变：2个家族患儿中THPO R99W为纯合子，第三个家族患儿中THPO R157X为纯合子。这两种突变都会导致患者血清中THPO的缺乏。对于2名存活的患者，在接受THPO受体激动剂治疗后，三岁造血功能得到改善。这些研究表明，THPO的双等位基因功能缺失突变导致BMF由于造血细胞外源性机制对移植无反应。这些研究为MPL-THPO通路在造血中的关键作用提供了进一步的支持，并强调了准确的遗传诊断对BMF治疗决策的重要性。
We report 5 individuals in 3 unrelated families with severe thrombocytopenia progressing to trilineage bone marrow failure (BMF). Four of the children received hematopoietic stem cell transplants and all showed poor graft function with persistent severe cytopenias even after repeated transplants with different donors. Exome and targeted sequencing identified mutations in the gene encoding thrombopoietin (THPO): THPO R99W, homozygous in affected children in 2 families, and THPO R157X, homozygous in the affected child in the third family. Both mutations result in a lack of THPO in the patients' serum. For the 2 surviving patients, improvement in trilineage hematopoiesis was achieved following treatment with a THPO receptor agonist. These studies demonstrate that biallelic loss-of-function mutations in THPO cause BMF, which is unresponsive to transplant due to a hematopoietic cell-extrinsic mechanism. These studies provide further support for the critical role of the MPL-THPO pathway in hematopoiesis and highlight the importance of accurate genetic diagnosis to inform treatment decisions for BMF.