Journal
BLOOD
Volume 135, Issue 2, Pages 133-144Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019001103
Keywords
-
Categories
Funding
- Cariplo Foundation [2013-0717, 2017-0920]
- US National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering [R01 EB016041-02]
- National Heart, Lung, and Blood Institute [R01 HL134829]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG 2016 18700]
- Special Program Molecular Clinical Oncology 5x1000 AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM)
- AIRC [21267]
- Fondazione Regionale Ricerca Biomedica (FRRB) [2015-0042]
- Italian Ministry of Health (Ricerca Finalizzata Giovani Ricercatori) [GR-2016-02363136]
- INCAPLbio 2015
- la Ligue Nationale Contre le Cancer
Ask authors/readers for more resources
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. 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 (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 Ca2+, 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 Ca2+ mobilization. In Mks from patients with CALR-mutated MPNs, defective interactions between mutant calreticulin, ERp57, and STIM1 activated SOCE and generated spontaneous cytosolic Ca2+ flows. In turn, this resulted in abnormal Mk proliferation that was reverted using a specific SOCE inhibitor. In summary, the abnormal SOCE regulation of Cat 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available