期刊
BLOOD
卷 131, 期 6, 页码 649-661出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-09-806356
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资金
- National Institute for Health Research Cambridge Biomedical Research Centre
- Bloodwise
- Cancer Research UK
- Wellcome Trust
- Cambridge Experimental Cancer Medicine Centre
- Leukemia & Lymphoma Society of America
- Bloodwise [15008]
- European Hematology Association
- European Research Council [ERC-2016-StG-715371]
- European Molecular Biology Laboratory Long-Term Fellowship [ALTF 1132-2015]
- Kay Kendall Leukaemia Fund
- British Heart Foundation [FS/09/039/27788] Funding Source: researchfish
- Cancer Research UK [21762] Funding Source: researchfish
- Medical Research Council [MC_PC_12009] Funding Source: researchfish
Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1-bp frameshift and generate a novel protein C terminus. In this study, we generated a conditional mouse knockin model of the most common CALR mutation, a 52-bp deletion. The mutant novel human C-terminal sequence is integrated into the otherwise intact mouse CALR gene and results in mutant CALR expression under the control of the endogenous mouse locus. CALR(del/+) mice develop a transplantable ET-like disease with marked thrombocytosis, which is associated with increased and morphologically abnormal megakaryocytes and increased numbers of phenotypically defined hematopoietic stem cells (HSCs). Homozygous CALR(del/del) mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALR(del/+) HSCs were more proliferative in vitro, but neither CALR(del/+) nor CALR(del/del) displayed a competitive transplantation advantage in primary or secondary recipient mice. These results demonstrate the consequences of heterozygous and homozygous CALR mutations and provide a powerful model for dissecting the pathogenesis of CALR-mutant ET and PMF.
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