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Rare type 1-like and type 2-like calreticulin mutants induce similar myeloproliferative neoplasms as prevalent type 1 and 2 mutants in mice
Oncogene ( IF 6.9 ) Pub Date : 2018-10-19 , DOI: 10.1038/s41388-018-0538-z
Katte Rao Toppaldoddi , Maira da Costa Cacemiro , Olivier Bluteau , Barbara Panneau-Schmaltz , Amélie Pioch , Delphine Muller , Jean-Luc Villeval , Hana Raslova , Stefan N. Constantinescu , Isabelle Plo , William Vainchenker , Caroline Marty

Frameshift mutations in the calreticulin (CALR) gene are present in 30% of essential thrombocythemia and myelofibrosis patients. The two most frequent mutations are CALR del52 (type 1, approximately 60%) and CALR ins5 (type 2, around 30%), but many other rarer mutations exist accounting each for less than 2% of all CALR mutations. Most of them are structurally classified as type 1-like and type 2-like CALR mutations according to the absence or presence of a residual wild-type calcium-binding motif and the modification of the alpha-helix structure. Yet, several key questions remain unanswered, especially the reason of such low frequencies of these other mutations. In an attempt to investigate specific pathogenic differences between type 1-like and type 2-like CALR mutations and del52 and ins5, we modeled two type 1-like (del34 and del46) and one type 2-like (del19) mutations in cell lines and in mice. All CALR mutants constitutively activate JAK2 and STAT5/3/1 in a similar way in the presence of the thrombopoietin receptor (MPL) and induced cytokine-independent cell growth but to a lesser extent with rare mutants over time. This correlates with reduced expression levels of rare CALR mutants compared to del52 and ins5. Lethally irradiated mice that were engrafted with bone marrow transduced with the different CALR mutations developed thrombocytosis, but to a much lesser extent with ins5 and the type 2-like CALR mutation. In contrast to type 2-like mice, type 1-like mice developed marked myelofibrosis and splenomegaly 10 months after engraftment. Similar to del52, type 1-like CALR mutations induced an expansion at an early stage of hematopoiesis compared to ins5 and type 2-like mutation. Thus, type 1-like and type 2-like CALR mutants structurally and functionally resemble del52 and ins5 mutants, respectively.



中文翻译:

罕见的1型和2型钙网蛋白突变体与小鼠中常见的1型和2型突变体诱导相似的骨髓增生性肿瘤

在30%的原发性血小板增多症和骨髓纤维化患者中存在钙网蛋白(CALR)基因的移码突变。两种最常见的突变是CALR del52(1型,约60%)和CALR ins5(2型,约30%),但存在许多其他罕见突变,每种突变均少于所有CALR突变的2%。它们中的大多数在结构上分为类1型和类2 CALR根据是否存在残留的野生型钙结合基序和α-螺旋结构的修饰进行突变。然而,一些关键问题仍未得到解答,特别是这些其他突变频率如此之低的原因。为了研究1型和2型CALR突变与del52ins5之间的特定致病性差异,我们模拟了两种1型(del34del46)和一种2型(del19)。)细胞系和小鼠中的突变。在血小板生成素受体(MPL)存在的情况下,所有CALR突变体都以相似的方式组成性激活JAK2和STAT5 / 3/1,并诱导细胞因子非依赖性细胞生长,但随着时间的推移,罕见突变体的程度较小。与del52和ins5相比,这与稀有CALR突变体的表达水平降低相关。植入了经不同CALR突变转导的骨髓的经放射辐照的小鼠发展为血小板增多症,但ins5和2型CALR突变程度较小。与2型小鼠相比,1型小鼠在移植后10个月出现明显的骨髓纤维化和脾肿大。与del52相似,类型为1的CALRins5和2型突变相比,这种突变在造血早期诱导了扩增。因此,1型和2型CALR突变体在结构和功能上分别类似于del52和ins5突变体。

更新日期:2018-10-19
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