Calreticulin del52 and ins5 knock-in mice recapitulate different myeloproliferative phenotypes observed in patients with MPN

Camélia Benlabiod, Maira da Costa Cacemiro, Audrey Nédélec, Valérie Edmond, Delphine Muller, Philippe Rameau, Laure Touchard, Patrick Gonin, Stefan N. Constantinescu, Hana Raslova, Jean-Luc Villeval, William Vainchenker, Isabelle Plo and Caroline Marty ()
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Camélia Benlabiod: INSERM, UMR 1287, Gustave Roussy
Maira da Costa Cacemiro: INSERM, UMR 1287, Gustave Roussy
Audrey Nédélec: Ludwig Institute for Cancer Research
Valérie Edmond: INSERM, UMR 1287, Gustave Roussy
Delphine Muller: INSERM, UMR 1287, Gustave Roussy
Philippe Rameau: Integrated Biology Core Facility, Gustave Roussy
Laure Touchard: Unité Mixte de Service AMMICA 3655/US 23, Gustave Roussy
Patrick Gonin: Unité Mixte de Service AMMICA 3655/US 23, Gustave Roussy
Stefan N. Constantinescu: Ludwig Institute for Cancer Research
Hana Raslova: INSERM, UMR 1287, Gustave Roussy
Jean-Luc Villeval: INSERM, UMR 1287, Gustave Roussy
William Vainchenker: INSERM, UMR 1287, Gustave Roussy
Isabelle Plo: INSERM, UMR 1287, Gustave Roussy
Caroline Marty: INSERM, UMR 1287, Gustave Roussy

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18691-3

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