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

Authors
  • El-Khoury, Mira1, 2, 3
  • Cabagnols, Xénia1, 2, 3
  • Mosca, Matthieu1, 2, 4
  • Vertenoeil, Gaëlle5, 6
  • Marzac, Christophe7
  • Favale, Fabrizia8
  • Bluteau, Olivier1, 2, 4
  • Lorre, Florence8
  • Tisserand, Amandine1, 2, 3
  • Rabadan Moraes, Graciela1, 2, 3
  • Ugo, Valérie9
  • Ianotto, Jean-Christophe10
  • Rey, Jerôme11
  • Solary, Eric1, 2, 4, 7
  • Roy, Lydia12
  • Rameau, Philippe2
  • Debili, Najet1, 2, 4
  • Pasquier, Florence1, 2, 4, 7
  • Casadevall, Nicole1, 2, 13
  • Marty, Caroline1, 2, 4
  • 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.

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