Hematopoietic expression of a chimeric murine‐human <scp>CALR</scp> oncoprotein allows the assessment of <scp>anti‐CALR</scp> antibody immunotherapies in vivo

Myeloproliferative neoplasms (MPNs) are characterized by a pathologic expansion of myeloid lineages. Mutations in JAK2, CALR and MPL genes known to be three prominent MPN disease drivers. Mutant (mutCALR) is an oncoprotein that interacts with activates the thrombopoietin receptor (MPL) represents attractive target for targeted therapy mutated MPN. We generated transgenic murine model conditional expression human mutant exon 9 (del52) from endogenous Calr locus. These mice develop essential thrombocythemia like phenotype marked thrombocytosis megakaryocytosis. The exacerbates age showing signs splenomegaly anemia. transplantable mutCALR stem cells show proliferative advantage when compared wild type cells. Transcriptome profiling hematopoietic revealed oncogenic inflammatory gene signatures. To demonstrate applicability animals immunotherapy, we treated monoclonal antibody raised against mutCALR. treatment lowered platelet cell counts mice. Secretion did not constitute significant sink. This animal only recapitulates but also serves as relevant testing immunotherapeutic strategies targeting epitopes