論文

国際誌
2019年3月29日

Mice with Calr mutations homologous to human CALR mutations only exhibit mild thrombocytosis.

Blood cancer journal
  • Kotaro Shide
  • Takuro Kameda
  • Ayako Kamiunten
  • Asami Oji
  • Yoshinori Ozono
  • Masaaki Sekine
  • Arata Honda
  • Akira Kitanaka
  • Keiichi Akizuki
  • Yuki Tahira
  • Kenichi Nakamura
  • Tomonori Hidaka
  • Yoko Kubuki
  • Hiroo Abe
  • Tadashi Miike
  • Hisayoshi Iwakiri
  • Yoshihiro Tahara
  • Mitsue Sueta
  • Satoru Hasuike
  • Shojiro Yamamoto
  • Kenji Nagata
  • Masahito Ikawa
  • Kazuya Shimoda
  • 全て表示

9
4
開始ページ
42
終了ページ
42
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41408-019-0202-z

Calreticulin (CALR) exon 9 frameshift mutations, commonly detected in essential thrombocythemia (ET) and primary myelofibrosis patients, activate signal transducer and activator of transcription (STAT) proteins in the presence of Myeloproliferative Leukemia Virus (MPL) and induce ET in vivo. Loss of the KDEL motif, an endoplasmic reticulum retention signal, and generation of many positively charged amino acids (AAs) in the mutated C-terminus are thought to be important for disease induction. To test this hypothesis, we generated mice harboring a Calr frameshift mutation using the CRISPR/Cas9 system. Deletion of 19-base pairs in exon 9 (c.1099-1117del), designated the del19 mutation, induced loss of the KDEL motif and generated many positively charged AAs, similar to human mutants. Calr del19 mice exhibited mild thrombocytosis, slightly increased megakaryocytes, and mild splenomegaly. In vitro experiments revealed that the murine CALR del19 mutant had a weaker ability to combine with murine MPL than the human CALR del52 mutant. Consequently, STAT5 activation was also very weak downstream of the murine mutant and murine MPL, and may be the reason for the mild disease severity. In summary, loss of the KDEL motif and positively charged AAs in the C-terminus of CALR is insufficient for MPL binding and ET development.

リンク情報
DOI
https://doi.org/10.1038/s41408-019-0202-z
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/30926777
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440999
ID情報
  • DOI : 10.1038/s41408-019-0202-z
  • PubMed ID : 30926777
  • PubMed Central 記事ID : PMC6440999

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