TY - JOUR
T1 - Different impact of calreticulin mutations on human hematopoiesis in myeloproliferative neoplasms
AU - El-Khoury, Mira
AU - Cabagnols, Xénia
AU - Mosca, Matthieu
AU - Vertenoeil, Gaëlle
AU - Marzac, Christophe
AU - Favale, Fabrizia
AU - Bluteau, Olivier
AU - Lorre, Florence
AU - Tisserand, Amandine
AU - Rabadan Moraes, Graciela
AU - Ugo, Valérie
AU - Ianotto, Jean Christophe
AU - Rey, Jerôme
AU - Solary, Eric
AU - Roy, Lydia
AU - Rameau, Philippe
AU - Debili, Najet
AU - Pasquier, Florence
AU - Casadevall, Nicole
AU - Marty, Caroline
AU - Constantinescu, Stefan N.
AU - Raslova, Hana
AU - Vainchenker, William
AU - Plo, Isabelle
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/7/30
Y1 - 2020/7/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85086780782&partnerID=8YFLogxK
U2 - 10.1038/s41388-020-1368-3
DO - 10.1038/s41388-020-1368-3
M3 - Article
C2 - 32572159
AN - SCOPUS:85086780782
SN - 0950-9232
VL - 39
SP - 5323
EP - 5337
JO - Oncogene
JF - Oncogene
IS - 31
ER -