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Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage.

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Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage. / Li, J; Prins, D; Park, HJ; Grinfeld, J; Gonzalez-Arias, C; Loughran, S; Dovey, OM; Klampfl, T; Bennett, C; Hamilton, TL; Pask, DC; Sneade, R; Williams, M; Aungier, J; Ghevaert, C; Vassiliou, GS; Kent, DG; Green, AR.

In: Blood, Vol. 131, No. 6, 08.02.2018, p. 649-661.

Research output: Contribution to journalArticlepeer-review

Harvard

Li, J, Prins, D, Park, HJ, Grinfeld, J, Gonzalez-Arias, C, Loughran, S, Dovey, OM, Klampfl, T, Bennett, C, Hamilton, TL, Pask, DC, Sneade, R, Williams, M, Aungier, J, Ghevaert, C, Vassiliou, GS, Kent, DG & Green, AR 2018, 'Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage.', Blood, vol. 131, no. 6, pp. 649-661. https://doi.org/10.1182/blood-2017-09-806356

APA

Li, J., Prins, D., Park, HJ., Grinfeld, J., Gonzalez-Arias, C., Loughran, S., Dovey, OM., Klampfl, T., Bennett, C., Hamilton, TL., Pask, DC., Sneade, R., Williams, M., Aungier, J., Ghevaert, C., Vassiliou, GS., Kent, DG., & Green, AR. (2018). Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage. Blood, 131(6), 649-661. https://doi.org/10.1182/blood-2017-09-806356

Vancouver

Li J, Prins D, Park HJ, Grinfeld J, Gonzalez-Arias C, Loughran S et al. Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage. Blood. 2018 Feb 8;131(6):649-661. https://doi.org/10.1182/blood-2017-09-806356

Author

Li, J ; Prins, D ; Park, HJ ; Grinfeld, J ; Gonzalez-Arias, C ; Loughran, S ; Dovey, OM ; Klampfl, T ; Bennett, C ; Hamilton, TL ; Pask, DC ; Sneade, R ; Williams, M ; Aungier, J ; Ghevaert, C ; Vassiliou, GS ; Kent, DG ; Green, AR. / Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage. In: Blood. 2018 ; Vol. 131, No. 6. pp. 649-661.

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@article{233d0ab3785947e398be687052c5a88c,
title = "Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage.",
abstract = "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. CALRdel/+ 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 CALRdel/del mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALRdel/+ HSCs were more proliferative in vitro, but neither CALRdel/+ nor CALRdel/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.",
author = "J Li and D Prins and HJ Park and J Grinfeld and C Gonzalez-Arias and S Loughran and OM Dovey and T Klampfl and C Bennett and TL Hamilton and DC Pask and R Sneade and M Williams and J Aungier and C Ghevaert and GS Vassiliou and DG Kent and AR Green",
year = "2018",
month = feb,
day = "8",
doi = "10.1182/blood-2017-09-806356",
language = "English",
volume = "131",
pages = "649--661",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "6",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Mutant calreticulin knockin mice develop thrombocytosis and myelofibrosis without a stem cell self-renewal advantage.

AU - Li, J

AU - Prins, D

AU - Park, HJ

AU - Grinfeld, J

AU - Gonzalez-Arias, C

AU - Loughran, S

AU - Dovey, OM

AU - Klampfl, T

AU - Bennett, C

AU - Hamilton, TL

AU - Pask, DC

AU - Sneade, R

AU - Williams, M

AU - Aungier, J

AU - Ghevaert, C

AU - Vassiliou, GS

AU - Kent, DG

AU - Green, AR

PY - 2018/2/8

Y1 - 2018/2/8

N2 - 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. CALRdel/+ 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 CALRdel/del mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALRdel/+ HSCs were more proliferative in vitro, but neither CALRdel/+ nor CALRdel/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.

AB - 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. CALRdel/+ 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 CALRdel/del mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALRdel/+ HSCs were more proliferative in vitro, but neither CALRdel/+ nor CALRdel/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.

U2 - 10.1182/blood-2017-09-806356

DO - 10.1182/blood-2017-09-806356

M3 - Article

VL - 131

SP - 649

EP - 661

JO - Blood

JF - Blood

SN - 0006-4971

IS - 6

ER -