Repository logo

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

Accepted version

Change log


Li, Juan 
Prins, Daniel 
Park, Hyun Jung 
Grinfeld, Jacob 
Gonzalez-Arias, Carlos 


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.



Animals, Calreticulin, Cell Self Renewal, Cells, Cultured, Hematopoietic Stem Cells, Homozygote, Leukocytosis, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Missense, Primary Myelofibrosis, Splenomegaly, Thrombocythemia, Essential, Thrombocytosis

Journal Title


Conference Name

Journal ISSN


Volume Title



American Society of Hematology
Kay Kendall Leukaemia Fund (KKL952)
Medical Research Council (MC_PC_12009)
Cancer Research Uk (None)
Cancer Research Uk (None)
Leukaemia & Lymphoma Research (13003)
Cancer Research UK (21762)
British Heart Foundation (None)
Bloodwise (15008)
European Research Council (715371)
Cancer Research UK (23015)