Mutations in the human calreticulin (CALR) gene represented by -1+2 frameshifting deletions and insertions in exon 9 are associated with myeloproliferative neoplasms (MPNs). Mutant CALR proteins induce thrombocytosis in vivo due to their ability to pathologically and persistently activate the thrombopoietin receptor (TpoR) and the JAK2-STAT5/3/1 pathway. Homologous murine Calr frame-shifting mutations generate a C-terminal sequence that is not absolutely identical to that of human CALR mutants, although we show it bears similar biophysical features. We demonstrate that the murine CALR mutants del52, ins5 and del61 also activate the TpoR-JAK-STAT pathway. Using the CRISPR/Cas9 system, we created the del61 endogenous murine Calr mutation, as well as other -1/+2 frameshift mutations in Ba/F3 cells. These led to autonomous growth in Ba/F3 TpoR, but not parental Ba/F3 cells and induced constitutive TpoR, JAK-STAT and weak MAP-kinase signaling. In this heterozygous system we show that excess wild-type CALR does not inhibit mutant CALR signaling. Pathologic signaling is associated with a decrease of cell surface TpoR levels, which explains weaker response of transformed cells to ligand. Our results support the use of mouse models using murine CALR mutants and demonstrate pathologic signaling induced by heterozygous CALR mutations in hematopoietic cells.