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

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.

Source: Blood - February 8, 2018 Category: Hematology Authors: Li, J., Prins, D., Park, H. J., Grinfeld, J., Gonzalez-Arias, C., Loughran, S., Dovey, O. M., Klampfl, T., Bennett, C., Hamilton, T. L., Pask, D. C., Sneade, R., Williams, M., Aungier, J., Ghevaert, C., Vassiliou, G. S., Kent, D. G., Green, A. R. Tags: Myeloid Neoplasia Source Type: research