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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 39 Issue 31 Pg. 5323-5337 (07 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32572159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CALR protein, human
• Calreticulin

Topics

• Calreticulin (adverse effects)
• Female
• Hematopoiesis (drug effects)
• Humans
• Male
• Mutation
• Myeloproliferative Disorders (genetics)