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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)133-144
Number of pages12
JournalBlood
Volume135
Issue number2
DOIs
Publication statusPublished - 2020

Keywords

  • calcium
  • calreticulin
  • endoplasmic reticulum protein 57
  • inositol trisphosphate
  • mitogen activated protein kinase 1
  • mitogen activated protein kinase 3
  • STAT5 protein
  • stromal interaction molecule 1
  • thrombopoietin
  • unclassified drug
  • Article
  • calcium cell level
  • calcium mobilization
  • cell proliferation
  • endoplasmic reticulum
  • enzyme linked immunosorbent assay
  • extracellular calcium
  • gene mutation
  • human
  • human cell
  • intracellular signaling
  • megakaryocyte
  • myeloproliferative neoplasm
  • pathophysiology
  • phenotype
  • priority journal
  • somatic mutation
  • store operated calcium entry
  • Western blotting

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