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Posted by star on 2019-11-08 15:44:45 Hits:226
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As we know in normal megakaryocytes, calreticulin regulates the activation of Store Operated Calcium Entry (SOCE) by interacting with ERp57 and STIM1.
While scientists from University of Pavia found that in CALR-mutated MPNs, defective interaction between mutant calreticulin and SOCE proteins promotes megakaryocyte proliferation. Their research has been published in Blood recently.
About one fourth of patients with essential thrombocythemia or primary myelofibrosis carry a somatic mutation of CALR, the gene encoding for calreticulin. A 52-bp deletion (Type I mutation) and a 5-bp insertion (Type II mutation) are the most frequent genetic lesions. 
The mechanism(s) by which a CALR mutation leads to a myeloproliferative phenotype has been clarified only in part. We studied the interaction between calreticulin and Store Operated Calcium (Ca2+) Entry (SOCE) machinery in megakaryocytes from healthy individuals and from patients with CALR-mutated myeloproliferative neoplasms. In megakaryocytes from healthy subjects, binding of recombinant human thrombopoietin to c-Mpl induced the activation of STAT5, AKT and ERK1/2, determining inositol triphosphate (IP3)-dependent Ca2+ release from the endoplasmic reticulum. This resulted in the dissociation of the ERp57-mediated complex between calreticulin and STIM1, a protein of the SOCE machinery that leads to Ca2+ mobilization. 
In megakaryocytes from patients with CALR-mutated myeloproliferative neoplasms, defective interactions between mutant calreticulin, ERp57, and STIM1 activated SOCE and generated spontaneous cytosolic Ca2+ flows. In turn, this resulted in abnormal megakaryocyte proliferation that was reverted employing a specific SOCE inhibitor.
In summary, the abnormal SOCE regulation of Ca2+ flows in megakaryocytes contributes to the pathophysiology of CALR-mutated myeloproliferative neoplasms. In perspective, SOCE may represent a new therapeutic target to counteract megakaryocyte proliferation and its clinical consequences in myeloproliferative neoplasms.
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