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Knock-in of murine Calr del52 induces essential thrombocythemia with slow-rising dominance in mice and reveals key role of Calr exon 9 in cardiac development

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Balligand, Thomas [UCL] Achouri, Younes [UCL] Pecquet, Christian [UCL] Gaudray, Gilles [UCL] Colau, Didier [UCL] Rahmani, Yacine [UCL] Stroobant, Vincent [UCL] Van Den Eynde, Benoît [UCL] Defour, Jean-Philippe [UCL] Constantinescu, Stefan N. [UCL]

Frameshifting mutations (−1/+2) of the calreticulin (CALR) gene are responsible for the development of essential thrombocythemia (ET) and primary myelofibrosis (PMF). The mutant CALR proteins activate the thrombopoietin receptor (TpoR) inducing cytokine-independent megakaryocyte progenitor proliferation. Here, we generated via CRISPR/Cas9 technology two knock-in mouse models that are heterozygous for a type-I murine Calr mutation. These mice exhibit an ET phenotype with elevated circulating platelets compared with wild-type controls, consistent with our previous results showing that murine CALR mutants activate TpoR. We also show that the mutant CALR proteins can be detected in plasma. The phenotype of Calr del52 is transplantable, and the Calr mutated hematopoietic cells have a slow-rising advantage over wild-type hematopoiesis. Importantly, a homozygous state of a type-1 Calr mutation is lethal at a late embryonic development stage, showing narrowed ventricular myocardium walls, similar to the murine Calr knockout phenotype, pointing to the C terminus of CALR as crucial for heart development.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2020
Language Anglais
Journal information "Leukemia" - Vol. 34, no. 2, p. 510-521 (2020)
Peer reviewed yes
Publisher Nature Publishing Group ((United Kingdom) London)
issn 0887-6924
e-issn 1476-5551
Publication status Publié
Affiliations UCL - SSS/DDUV/SIGN - Cell signalling
UCL - SSS/DDUV/GECE - Génétique cellulaire
UCL - SSS/DDUV/LPAD - Liver and pancreas differentiation
UCL - (SLuc) Service de biologie hématologique
UCL - (SLuc) Service d'hématologie
Keywords Cancer Research ; Hematology ; Calreticulin ; Thrombopoieisis
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Bibliographic reference Balligand, Thomas ; Achouri, Younes ; Pecquet, Christian ; Gaudray, Gilles ; Colau, Didier ; et. al. Knock-in of murine Calr del52 induces essential thrombocythemia with slow-rising dominance in mice and reveals key role of Calr exon 9 in cardiac development. In: Leukemia, Vol. 34, no. 2, p. 510-521 (2020)
Permanent URL http://hdl.handle.net/2078.1/220787