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

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

doi:https://doi.org/10.1038/s41408-019-0202-z

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

Shide, Kotaro; Kameda, Takuro; Kamiunten, Ayako et al.

Blood Cancer Journal, 2019, 9(4), 42

Number of Access:1,982（2025-08-22 02:12 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/78559

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Title	Mice with Calr mutations homologous to human CALR mutations only exhibit mild thrombocytosis
Creator	NRID 1000020468028 1000020468028 CreatorName Shide, Kotaro
	NRID 1000030468029 1000030468029 CreatorName Kameda, Takuro
	NRID 1000030800750 1000030800750 CreatorName Kamiunten, Ayako
	NRID 1000050803417 1000050803417 CreatorName Oji, Asami
	NRID 1000020839394 1000020839394 CreatorName Ozono, Yoshinori
	CreatorName Sekine, Masaaki
	NRID 1000010373367 1000010373367 CreatorName Honda, Arata
	NRID 1000070343308 1000070343308 CreatorName Kitanaka, Akira
	CreatorName Akizuki, Keiichi
	CreatorName Tahira, Yuki
	CreatorName Nakamura, Kenichi
	NRID 1000040381115 1000040381115 CreatorName Hidaka, Tomonori
	NRID 1000000284836 1000000284836 CreatorName Kubuki, Yoko
	CreatorName Abe, Hiroo
	CreatorName Miike, Tadashi
	CreatorName Iwakiri, Hisayoshi
	CreatorName Tahara, Yoshihiro
	CreatorName Sueta, Mitsue
	NRID 1000050381067 1000050381067 CreatorName Hasuike, Satoru
	CreatorName Yamamoto, Shojiro
	NRID 1000000372798 1000000372798 CreatorName Nagata, Kenji
	NRID 1000020304066 1000020304066 ORCID 0000-0001-9859-6217 0000-0001-9859-6217 researchmap permalink read0054910 read0054910 Scopus Author ID 16689054500 16689054500 CreatorName Ikawa, Masahito
	NRID 1000090311844 1000090311844 CreatorName Shimoda, Kazuya
Description	Shide, K., Kameda, T., Kamiunten, A. et al. Mice with Calr mutations homologous to human CALR mutations only exhibit mild thrombocytosis. Blood Cancer J. 9, 42 (2019). https://doi.org/10.1038/s41408-019-0202-z
Abstract	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.
Publisher	Springer Nature
Source Title	Blood Cancer Journal
Volume (Issue)	9(4)
Page	42
Date of Issued	2019-03-29
Language	English
Handle URL	https://hdl.handle.net/11094/78559
eISSN	20445385
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1038/s41408-019-0202-z
Relation.isIdenticalTo	PMID 30926777
Access Rights	open access
CopyRight	© 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Blood Cancer Journal. 2019, 9(4), p. 42
DC.title	Mice with Calr mutations homologous to human CALR mutations only exhibit mild thrombocytosis
DC.creator	Shide, Kotaro
	Kameda, Takuro
	Kamiunten, Ayako
	Oji, Asami
	Ozono, Yoshinori
	Sekine, Masaaki
	Honda, Arata
	Kitanaka, Akira
	Akizuki, Keiichi
	Tahira, Yuki
	Nakamura, Kenichi
	Hidaka, Tomonori
	Kubuki, Yoko
	Abe, Hiroo
	Miike, Tadashi
	Iwakiri, Hisayoshi
	Tahara, Yoshihiro
	Sueta, Mitsue
	Hasuike, Satoru
	Yamamoto, Shojiro
	Nagata, Kenji
	Ikawa, Masahito
	Shimoda, Kazuya
DC.publisher	Springer Nature
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2019-03-29
DC.identifier	https://doi.org/10.1038/s41408-019-0202-z
DC.description	Shide, K., Kameda, T., Kamiunten, A. et al. Mice with Calr mutations homologous to human CALR mutations only exhibit mild thrombocytosis. Blood Cancer J. 9, 42 (2019). https://doi.org/10.1038/s41408-019-0202-z
DCTERMS.abstract	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.
DC.rights	© 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	78559
citation_title	Mice with Calr mutations homologous to human CALR mutations only exhibit mild thrombocytosis
citation_author	Shide, Kotaro
	Kameda, Takuro
	Kamiunten, Ayako
	Oji, Asami
	Ozono, Yoshinori
	Sekine, Masaaki
	Honda, Arata
	Kitanaka, Akira
	Akizuki, Keiichi
	Tahira, Yuki
	Nakamura, Kenichi
	Hidaka, Tomonori
	Kubuki, Yoko
	Abe, Hiroo
	Miike, Tadashi
	Iwakiri, Hisayoshi
	Tahara, Yoshihiro
	Sueta, Mitsue
	Hasuike, Satoru
	Yamamoto, Shojiro
	Nagata, Kenji
	Ikawa, Masahito
	Shimoda, Kazuya
citation_publisher	Springer Nature
citation_language	English
citation_date	2019-03-29
citation_journal_title	Blood Cancer Journal
citation_volume	9
citation_issue	4
citation_firstpage	42
citation_doi	https://doi.org/10.1038/s41408-019-0202-z
citation_pmid	30926777
citation_public_url	https://hdl.handle.net/11094/78559

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

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