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 MartyStefan N. Constantinescu, Hana Raslova, William Vainchenker, Isabelle Plo

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    13 Citations (Scopus)

    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)5323-5337
    Nombre de pages15
    journalOncogene
    Volume39
    Numéro de publication31
    Les DOIs
    étatPublié - 30 juil. 2020

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