Approximately one-fourth of patients with essential thrombocythemia or primary myelofibrosis carry a somatic mutation of the calreticulin gene (CALR), the gene encoding for calreticulin. A52-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 (Ca21) entry (SOCE) machinery in megakaryocytes (Mks) from healthy individuals and from patients with CALR-mutated myeloproliferative neoplasms (MPNs). In Mks from healthy subjects, binding of recombinant human thrombopoietin to c-Mpl induced the activation of signal transducer and activator of transcription 5, AKT, and extracellular signal-regulated kinase 1/2, determining inositol triphosphate-dependent Ca21 release from the endoplasmic reticulum (ER). This resulted in the dissociation of the ER protein 57 (ERp57)-mediated complex between calreticulin and stromal interaction molecule 1 (STIM1), a protein of the SOCE machinery that leads to Ca21 mobilization. In Mks from patients with CALR-mutated MPNs, defective interactions between mutant calreticulin, ERp57, and STIM1 activated SOCE and generated spontaneous cytosolic Ca21 flows. In turn, this resulted in abnormal Mk proliferation that was reverted using a specific SOCE inhibitor. In summary, the abnormal SOCE regulation of Ca21 flows in Mks contributes to the pathophysiology of CALR-mutated MPNs. In perspective, SOCE may represent a new therapeutic target to counteract Mk proliferation and its clinical consequences in MPNs.
Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients with myeloproliferative neoplasms / C.A. Di Buduo, V. Abbonante, C. Marty, F. Moccia, E. Rumi, D. Pietra, P.M. Soprano, D. Lim, D. Cattaneo, A. Iurlo, U. Gianelli, G. Barosi, V. Rosti, I. Plo, M. Cazzola, A. Balduini. - In: BLOOD. - ISSN 0006-4971. - 135:2(2020 Jan 09), pp. 133-144. [10.1182/blood.2019001103]
|Titolo:||Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients with myeloproliferative neoplasms|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||9-gen-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1182/blood.2019001103|
|Appare nelle tipologie:||01 - Articolo su periodico|