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

Autor: El-Khoury M; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris Diderot (Paris 7), UMR1287, Gustave Roussy, Villejuif, France., Cabagnols X; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris Diderot (Paris 7), UMR1287, Gustave Roussy, Villejuif, France., Mosca M; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France., Vertenoeil G; Ludwig Institute for Cancer Research Brussels, Brussels, Belgium.; Université Catholique de Louvain and de Duve Institute, Brussels, Belgium., Marzac C; Département d'Hématologie, Gustave Roussy, Villejuif, France., Favale F; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, UMR_S 938, Paris, France., Bluteau O; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France., Lorre F; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, UMR_S 938, Paris, France., Tisserand A; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris Diderot (Paris 7), UMR1287, Gustave Roussy, Villejuif, France., Rabadan Moraes G; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris Diderot (Paris 7), UMR1287, Gustave Roussy, Villejuif, France., Ugo V; CHU Angers, Laboratoire d'Hématologie, Angers, France., Ianotto JC; CHRU Brest, service d'Hématologie, Brest, France., Rey J; Département d'Hématologie, Institut Paoli Calmettes, Service d'Hématologie, Marseille, France., Solary E; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France.; Département d'Hématologie, Gustave Roussy, Villejuif, France., Roy L; Assistance Publique Hôpitaux de Paris, CHU Henri Mondor, Service d'Hématologie, Créteil, France., Rameau P; Gustave Roussy, Villejuif, France., Debili N; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France., Pasquier F; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France.; Département d'Hématologie, Gustave Roussy, Villejuif, France., Casadevall N; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Laboratoire d'Hématologie, Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris, Paris, France., Marty C; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France., Constantinescu SN; Ludwig Institute for Cancer Research Brussels, Brussels, Belgium.; Université Catholique de Louvain and de Duve Institute, Brussels, Belgium.; WELBIO (Walloon Excellence in Life Sciences and Biotechnology), Brussels, Belgium., Raslova H; INSERM, UMR1287, Villejuif, France.; Gustave Roussy, Villejuif, France.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France., Vainchenker W; INSERM, UMR1287, Villejuif, France. william.vainchenker@gustaveroussy.fr.; Gustave Roussy, Villejuif, France. william.vainchenker@gustaveroussy.fr.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France. william.vainchenker@gustaveroussy.fr., Plo I; INSERM, UMR1287, Villejuif, France. isabelle.plo@gustaveroussy.fr.; Gustave Roussy, Villejuif, France. isabelle.plo@gustaveroussy.fr.; Université Paris XI, UMR1287, Gustave Roussy, Villejuif, France. isabelle.plo@gustaveroussy.fr.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2020 Jul; Vol. 39 (31), pp. 5323-5337. Date of Electronic Publication: 2020 Jun 22.
DOI: 10.1038/s41388-020-1368-3
Abstrakt: 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.
Databáze: MEDLINE
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