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Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients withmyeloproliferative neoplasms.
Blood 2019 October 25
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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