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Knock-in of murine Calr del52 induces essential thrombocythemia with slow-rising dominance in mice and reveals key role of Calr exon 9 in cardiac development.

小鼠Calr del52的敲入诱导小鼠原发性血小板增多症,具有缓慢上升的优势,并揭示了Calr外显子9在心脏发育中的关键作用。

  • 影响因子:6.08
  • DOI:10.1038/s41375-019-0538-1
  • 作者列表:"Balligand T","Achouri Y","Pecquet C","Gaudray G","Colau D","Hug E","Rahmani Y","Stroobant V","Plo I","Vainchenker W","Kralovics R","Van den Eynde BJ","Defour JP","Constantinescu SN
  • 发表时间:2020-02-01
Abstract

:Frameshifting mutations (-1/+2) of the calreticulin (CALR) gene are responsible for the development of essential thrombocythemia (ET) and primary myelofibrosis (PMF). The mutant CALR proteins activate the thrombopoietin receptor (TpoR) inducing cytokine-independent megakaryocyte progenitor proliferation. Here, we generated via CRISPR/Cas9 technology two knock-in mouse models that are heterozygous for a type-I murine Calr mutation. These mice exhibit an ET phenotype with elevated circulating platelets compared with wild-type controls, consistent with our previous results showing that murine CALR mutants activate TpoR. We also show that the mutant CALR proteins can be detected in plasma. The phenotype of Calr del52 is transplantable, and the Calr mutated hematopoietic cells have a slow-rising advantage over wild-type hematopoiesis. Importantly, a homozygous state of a type-1 Calr mutation is lethal at a late embryonic development stage, showing narrowed ventricular myocardium walls, similar to the murine Calr knockout phenotype, pointing to the C terminus of CALR as crucial for heart development.

摘要

: 钙网蛋白 (CALR) 基因的移码突变 (-1/+ 2) 负责原发性血小板增多症 (ET) 和原发性骨髓纤维化 (PMF) 的发展。突变型CALR蛋白激活血小板生成素受体 (TpoR) 诱导细胞因子非依赖性巨核细胞祖细胞增殖。在这里,我们通过CRISPR/Cas9技术产生了两种敲入小鼠模型,它们是I型鼠Calr突变的杂合模型。与野生型对照相比,这些小鼠表现出具有升高的循环血小板的ET表型,这与我们先前显示鼠CALR突变体激活TpoR的结果一致。我们还表明突变CALR蛋白可以在血浆中检测到。Calrdel52的表型是可移植的,并且Calr突变的造血细胞相对于野生型造血具有缓慢上升的优势。重要的是,1型Calr突变的纯合状态在胚胎发育后期是致命的,显示出狭窄的心肌壁,类似于鼠Calr敲除表型,指出CALR的C末端对心脏发育至关重要。

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影响因子:3.70
发表时间:2020-01-01
DOI:10.1093/ndt/gfy373
作者列表:["Caluwé R","Verbeke F","De Vriese AS"]

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影响因子:2.36
发表时间:2020-01-01
来源期刊:Platelets
DOI:10.1080/09537104.2019.1572875
作者列表:["Wang L","Xu L","Hao H","Jansen AJG","Liu G","Li H","Liu X","Zhao Y","Peng J","Hou M"]

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