AI Article Synopsis

  • - The study examines how mutations in calreticulin (CALRm) impact patients with essential thrombocythemia and myelofibrosis, showing that these mutations primarily affect blood cells and lead to early clonal dominance in hematopoietic stem and progenitor cells (HSPC).
  • - Type 1 CALRm spreads more easily in lymphoid cells than type 2 CALRm and is linked to a greater increase in various blood progenitors, while both types increase megakaryocytic progenitors and show different effects on signaling pathways.
  • - Results indicate that CALRm mutations serve as both initial and phenotypic events in the disease progression, with type 1 CALRm exhibiting a stronger influence on blood

Article 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.

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Source
http://dx.doi.org/10.1038/s41388-020-1368-3DOI Listing

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