Different impact of calreticulin mutations on human hematopoiesis in myeloproliferative neoplasms.

Mira El-Khoury; Xénia Cabagnols; Matthieu Mosca; Gaëlle Vertenoeil; Christophe Marzac; Fabrizia Favale; Olivier Bluteau; Florence Lorre; Amandine Tisserand; Graciela Rabadan Moraes; Valérie Ugo; Jean-Christophe Ianotto; Jerôme Rey; Eric Solary; Lydia Roy; Philippe Rameau; Najet Debili; Florence Pasquier; Nicole Casadevall; Caroline Marty; Stefan N Constantinescu; Hana Raslova; William Vainchenker; Isabelle Plo

doi:10.1038/s41388-020-1368-3

Publisher Website

Different impact of calreticulin mutations on human hematopoiesis in myeloproliferative neoplasms.

Authors

El-Khoury, Mira^{1, 2, 3}
Cabagnols, Xénia^{1, 2, 3}
Mosca, Matthieu^{1, 2, 4}
Vertenoeil, Gaëlle^{5, 6}
Marzac, Christophe⁷
Favale, Fabrizia⁸
Bluteau, Olivier^{1, 2, 4}
Lorre, Florence⁸
Tisserand, Amandine^{1, 2, 3}
Rabadan Moraes, Graciela^{1, 2, 3}
Ugo, Valérie⁹
Ianotto, Jean-Christophe¹⁰
Rey, Jerôme¹¹
Solary, Eric^{1, 2, 4, 7}
Roy, Lydia¹²
Rameau, Philippe²
Debili, Najet^{1, 2, 4}
Pasquier, Florence^{1, 2, 4, 7}
Casadevall, Nicole^{1, 2, 13}
Marty, Caroline^{1, 2, 4}
Constantinescu, Stefan N^{5, 6, 14}
Raslova, Hana^{1, 2, 4}
Vainchenker, William^{15, 16, 17}
Plo, Isabelle^{18, 19, 20}

And 4 more

¹ INSERM, UMR1287, Villejuif, France. , (France)
² Gustave Roussy, Villejuif, France. , (France)
³ Université Paris Diderot (Paris 7), UMR1287, Gustave Roussy, Villejuif, France. , (France)
⁴ Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France. , (France)
⁵ Ludwig Institute for Cancer Research Brussels, Brussels, Belgium. , (Belgium)
⁶ Université Catholique de Louvain and de Duve Institute, Brussels, Belgium. , (Belgium)
⁷ Département d'Hématologie, Gustave Roussy, Villejuif, France. , (France)
⁸ Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, UMR_S 938, Paris, France. , (France)
⁹ CHU Angers, Laboratoire d'Hématologie, Angers, France. , (France)
¹⁰ CHRU Brest, service d'Hématologie, Brest, France. , (France)
¹¹ Département d'Hématologie, Institut Paoli Calmettes, Service d'Hématologie, Marseille, France. , (France)
¹² Assistance Publique Hôpitaux de Paris, CHU Henri Mondor, Service d'Hématologie, Créteil, France. , (France)
¹³ Laboratoire d'Hématologie, Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris, Paris, France. , (France)
¹⁴ WELBIO (Walloon Excellence in Life Sciences and Biotechnology), Brussels, Belgium. , (Belgium)
¹⁵ INSERM, UMR1287, Villejuif, France. [email protected] , (France)
¹⁶ Gustave Roussy, Villejuif, France. [email protected] , (France)
¹⁷ Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France. [email protected] , (France)
¹⁸ INSERM, UMR1287, Villejuif, France. [email protected] , (France)
¹⁹ Gustave Roussy, Villejuif, France. [email protected] , (France)
²⁰ Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France. [email protected] , (France)

Type

Published Article

Journal

Oncogene

Publisher

Nature Publishing Group UK

Publication Date

Jun 22, 2020

Identifiers

DOI: 10.1038/s41388-020-1368-3

PMID: 32572159

Source

Medline

Language

English

License

Unknown

Abstract

Mutations of calreticulin (CALRm) define a subtype of myeloproliferative neoplasms (MPN). We studied the biological and genetic features of CALR-mutated essential thrombocythemia and myelofibrosis patients. In most cases, CALRm were found in granulocytes, monocytes, B and NK cells, but also in T cells. However, the type 1 CALRm spreads more easily than the type 2 CALRm in lymphoid cells. The CALRm were also associated with an early clonal dominance at the level of hematopoietic stem and progenitor cells (HSPC) with no significant increase during granulo/monocytic differentiation in most cases. Moreover, we found that half of type 2 CALRm patients harbors some homozygous progenitors. Those patients were associated with a higher clonal dominance during granulo/monocytic differentiation than patients with only heterozygous type 2 CALRm progenitors. When associated mutations were present, CALRm were the first genetic event suggesting that they are both the initiating and phenotypic event. In blood, type 1 CALRm led to a greater increased number of all types of progenitors compared with the type 2 CALRm. However, both types of CALRm induced an increase in megakaryocytic progenitors associated with a ruxolitinib-sensitive independent growth and with a mild constitutive signaling in megakaryocytes. At the transcriptional level, type 1 CALRm seems to deregulate more pathways than the type 2 CALRm in megakaryocytes. Altogether, our results show that CALRm modify both the HSPC and megakaryocyte biology with a stronger effect for type 1 than for type 2 CALRm.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. This record was last updated on 07/03/2020 and may not reflect the most current and accurate biomedical/scientific data available from NLM. The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/32572159

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