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In more than 80% of patients with myeloproliferative neoplasms (MPN), mutations in the Janus kinase 2 (JAK2), myeloproliferative leukemia virus (MPL), and calreticulin (CALR) genes have been reported. These mutations seem to contribute to the pathogenesis of MPN through the constitutive activation of the JAK/signal transducer and activator of transcription (STAT) signaling pathway.1 Mutant CALR has been shown to bind to MPL and activate downstream signaling pathways that lead to the induction of MPN pathology in mouse models.2 As far as the role of these genes in normal hematopoiesis is concerned, knockdown of Jak2 or Mpl in mouse models completely abolishes hematopoiesis.2 However, the effect of CALR deficiency in normal hematopoiesis remains unknown, as Calr-knockout animals die before birth.
To determine the role of CALR in normal hematopoiesis, Kotaro Shide et al.2 generated a mouse model in which only hematopoietic cells lack Calr expression. The authors also further explored the role of CALR in MPN pathogenesis by generating CALRdel52 mutant mice with Calr haploinsufficiency mimicking human MPN. The results of this study were published in Blood and are summarized below.
Transgenic mouse models
Exclusive CALR knockdown in hematopoietic cells induces extramedullary hematopoiesis
Bone marrow findings:
Spleen findings:
CALR haploinsufficiency increases the self-renewal of hematopoietic stem cells
CALR haploinsufficiency is needed for CALR mutation-induced MPN pathology
The results of this preclinical study indicate that lack of CALR expression exclusively in hematopoietic cells results in significant extramedullary hematopoiesis in the spleen. Moreover, the authors showed that CALR haploinsufficiency enhances the self-renewing capacity of hematopoietic stem cells and compensates for the reduced self-renewal capacity induced by the CALRdel52 mutation. Furthermore, only mice carrying both the CALRdel52 mutation and CALR haploinsufficiency (as seen in patients) develop an MPN-like phenotype with thrombocytosis, increased numbers of megakaryocytes, and enhanced growth of bone marrow stem cells.
References
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