Hematopoietic expression of a chimeric murine-human CALR oncoprotein allows the assessment of anti-CALR antibody immunotherapies in vivo
| Autor: | Harini Nivarthi, Oleh Zagrijtschuk, Eva Hug, Christoph J. Binder, Cecilia Varga, Andrea Majoros, D. Tsiantoulas, Anoop Kavirayani, Sarada Achyutuni, Ruochen Jia, Christina Schueller, Michael Schuster, Christoph Bock, Martin Senekowitsch, Robert Kralovics |
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| Rok vydání: | 2021 |
| Předmět: |
Blood Platelets
medicine.drug_class Transgene medicine.medical_treatment Recombinant Fusion Proteins Mice Transgenic Monoclonal antibody Epitope 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Gene Knock-In Techniques Molecular Targeted Therapy Frameshift Mutation Sequence Deletion Thrombopoietin receptor biology Antibodies Monoclonal Hematology Immunotherapy Exons Hematopoietic Stem Cells Mice Inbred C57BL Haematopoiesis Disease Models Animal 030220 oncology & carcinogenesis Radiation Chimera Splenomegaly biology.protein Cancer research Stem cell Antibody Calreticulin Transcriptome 030215 immunology Thrombocythemia Essential |
| Zdroj: | American journal of hematologyREFERENCES. 96(6) |
| ISSN: | 1096-8652 |
| Popis: | Myeloproliferative neoplasms (MPNs) are characterized by a pathologic expansion of myeloid lineages. Mutations in JAK2, CALR and MPL genes are known to be three prominent MPN disease drivers. Mutant CALR (mutCALR) is an oncoprotein that interacts with and activates the thrombopoietin receptor (MPL) and represents an attractive target for targeted therapy of CALR mutated MPN. We generated a transgenic murine model with conditional expression of the human mutant exon 9 (del52) from the murine endogenous Calr locus. These mice develop essential thrombocythemia like phenotype with marked thrombocytosis and megakaryocytosis. The disease exacerbates with age showing prominent signs of splenomegaly and anemia. The disease is transplantable and mutCALR stem cells show proliferative advantage when compared to wild type stem cells. Transcriptome profiling of hematopoietic stem cells revealed oncogenic and inflammatory gene expression signatures. To demonstrate the applicability of the transgenic animals for immunotherapy, we treated mice with monoclonal antibody raised against the human mutCALR. The antibody treatment lowered platelet and stem cell counts in mutant mice. Secretion of mutCALR did not constitute a significant antibody sink. This animal model not only recapitulates human MPN but also serves as a relevant model for testing immunotherapeutic strategies targeting epitopes of the human mutCALR. |
| Databáze: | OpenAIRE |
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