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From the same journal

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

Research output: Contribution to journalArticle

Author(s)

  • J Li
  • D Prins
  • HJ Park
  • J Grinfeld
  • C Gonzalez-Arias
  • S Loughran
  • OM Dovey
  • T Klampfl
  • C Bennett
  • TL Hamilton
  • DC Pask
  • R Sneade
  • M Williams
  • J Aungier
  • C Ghevaert
  • GS Vassiliou
  • DG Kent
  • AR Green

Department/unit(s)

Publication details

JournalBlood
DateAccepted/In press - 15 Dec 2017
DatePublished (current) - 8 Feb 2018
Issue number6
Volume131
Number of pages13
Pages (from-to)649-661
Original languageEnglish

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.

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