Different impact of calreticulin mutations on human hematopoiesis in myeloproliferative neoplasms

Mutations of calreticulin (CALRm) define a subtype of myeloproliferative neoplasms (MPN). We studied the biological and genetic features ofCALR-mutated essential thrombocythemia and myelofibrosis patients. In most cases,CALRmwere found in granulocytes, monocytes, B and NK cells, but also in T cells. However, the type 1CALRmspreads more easily than the type 2CALRmin lymphoid cells. TheCALRmwere 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 2CALRmpatients harbors some homozygous progenitors. Those patients were associated with a higher clonal dominance during granulo/monocytic differentiation than patients with only heterozygous type 2CALRmprogenitors. When associated mutations were present,CALRmwere the first genetic event suggesting that they are both the initiating and phenotypic event. In blood, type 1CALRmled to a greater increased number of all types of progenitors compared with the type 2CALRm. However, both types ofCALRminduced 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 1CALRmseems to deregulate more pathways than the type 2CALRmin megakaryocytes. Altogether, our results show thatCALRmmodify both the HSPC and megakaryocyte biology with a stronger effect for type 1 than for type 2CALRm.