Thrombopoietin is required for full phenotype expression in a JAK2V617F transgenic mouse model of polycythemia vera
| Autor: | Wanke Zhao, Akil Merchant, Donna M. Williams, Jerry L. Spivak, Linda S. Resar, Alison R. Moliterno, Zhizhuang Joe Zhao, Ophelia Rogers, Amy S. Duffield |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Physiology Neutrophils Hematologic Cancers and Related Disorders White Blood Cells Mice 0302 clinical medicine Polycythemia vera Animal Cells hemic and lymphatic diseases Immune Physiology Medicine and Health Sciences Polycythemia Vera Thrombocytosis Multidisciplinary Stem Cells Hematopoietic stem cell Animal Models Hematology Body Fluids Haematopoiesis Phenotypes medicine.anatomical_structure Blood Phenotype Experimental Organism Systems Oncology Thrombopoietin 030220 oncology & carcinogenesis Medicine Stem cell Cellular Types Anatomy Receptors Thrombopoietin Research Article Thrombocythemia Essential Genetically modified mouse Platelets Science Immune Cells Immunology Mouse Models Mice Transgenic Biology Research and Analysis Methods Blood Plasma 03 medical and health sciences Model Organisms medicine Genetics Animals Humans Myelofibrosis Thrombopoietin receptor Blood Cells Myeloproliferative Disorders Biology and Life Sciences Cancers and Neoplasms Cell Biology Janus Kinase 2 medicine.disease Hematopoietic Stem Cells Mice Inbred C57BL Disease Models Animal 030104 developmental biology Primary Myelofibrosis Mutation Cancer research Animal Studies Spleen |
| Zdroj: | PLoS ONE PLoS ONE, Vol 15, Iss 6, p e0232801 (2020) |
| ISSN: | 1932-6203 |
| Popis: | The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis are hematopoietic stem cell disorders and share driver mutations that either directly activate the thrombopoietin receptor, MPL, or activate it indirectly through gain-of-function mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, MPL surface expression in hematopoietic stem cells is also reduced in the myeloproliferative neoplasms due to abnormal post-translational glycosylation and premature destruction of JAK2, suggesting that the myeloproliferative neoplasms are disorders of MPL processing since MPL is the only hematopoietic growth factor receptor in hematopoietic stem cells. To examine this possibility, we genetically manipulated MPL expression and maturation in a JAK2V617F transgenic mouse model of polycythemia vera. Elimination of MPL expression completely abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could only be partially restored by expression of one MPL allele. Most importantly, elimination of thrombopoietin gene expression abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could be completely restored by expression of a single thrombopoietin allele. These data indicate that polycythemia vera is in part a thrombopoietin-dependent disorder and that targeting the MPL-thrombopoietin axis could be an effective, nonmyelotoxic therapeutic strategy in this disorder. |
| Databáze: | OpenAIRE |
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