Calreticulin del52 and ins5 knock-in mice recapitulate different myeloproliferative phenotypes observed in patients with MPN
| Autor: | Caroline Marty, Isabelle Plo, Audrey Nedelec, Laure Touchard, Camelia Benlabiod, Hana Raslova, Stefan N. Constantinescu, Philippe Rameau, Maira da Costa Cacemiro, William Vainchenker, Jean-Luc Villeval, Valérie Edmond, Delphine Muller, Patrick Gonin |
|---|---|
| Přispěvatelé: | UCL - SSS/DDUV/SIGN - Cell signalling, UCL - (SLuc) Service d'hématologie |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Science General Physics and Astronomy Article General Biochemistry Genetics and Molecular Biology Frameshift mutation Myeloproliferative disease 03 medical and health sciences Mice 0302 clinical medicine Megakaryocyte Gene knockin medicine Animals Humans Cancer models Myelofibrosis lcsh:Science Sequence Deletion Haematological cancer Multidisciplinary biology Essential thrombocythemia Homozygote Hematopoietic stem cell General Chemistry Janus Kinase 2 medicine.disease Hematopoietic Stem Cells Molecular biology Extramedullary hematopoiesis Mice Inbred C57BL Disease Models Animal Mutagenesis Insertional 030104 developmental biology medicine.anatomical_structure Phenotype Primary Myelofibrosis 030220 oncology & carcinogenesis biology.protein Female lcsh:Q Calreticulin Thrombocythemia Essential |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020) Nature communications, Vol. 11, no. 1, p. 4886 [1-15] (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Somatic mutations in the calreticulin (CALR) gene are associated with approximately 30% of essential thrombocythemia (ET) and primary myelofibrosis (PMF). CALR mutations, including the two most frequent 52 bp deletion (del52) and 5 bp insertion (ins5), induce a frameshift to the same alternative reading frame generating new C-terminal tails. In patients, del52 and ins5 induce two phenotypically distinct myeloproliferative neoplasms (MPNs). They are equally found in ET, but del52 is more frequent in PMF. We generated heterozygous and homozygous conditional inducible knock-in (KI) mice expressing a chimeric murine CALR del52 or ins5 with the human mutated C-terminal tail to investigate their pathogenic effects on hematopoiesis. Del52 induces greater phenotypic changes than ins5 including thrombocytosis, leukocytosis, splenomegaly, bone marrow hypocellularity, megakaryocytic lineage amplification, expansion and competitive advantage of the hematopoietic stem cell compartment. Homozygosity amplifies these features, suggesting a distinct contribution of homozygous clones to human MPNs. Moreover, homozygous del52 KI mice display features of a penetrant myelofibrosis-like disorder with extramedullary hematopoiesis linked to splenomegaly, megakaryocyte hyperplasia and the presence of reticulin fibers. Overall, modeling del52 and ins5 mutations in mice successfully recapitulates the differences in phenotypes observed in patients. Calreticulin del52 and ins5 mutations induce two phenotypically distinct myeloproliferative neoplasms in patients. Here the authors show that modeling these mutations in knock-in mice recapitulate the two diseases and highlight how they impact the different hematopoietic compartments. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|