Inherited transmission of the CSF3R T618I mutational hotspot in familial chronic neutrophilic leukemia

• Published in: Blood Vol. 134; no. 26; pp. 2414 - 2416
• Main Authors: Duployez, Nicolas, Willekens, Christophe, Plo, Isabelle, Marceau-Renaut, Alice, de Botton, Stéphane, Fenwarth, Laurène, Boyer, Thomas, Huet, Guillemette, Nibourel, Olivier, Rose, Christian, Nelken, Brigitte, Quesnel, Bruno, Preudhomme, Claude
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.12.2019; American Society of Hematology
• Subjects: Adolescent; Adult; Child; Female; Genetic Predisposition to Disease; Humans; Leukemia, Neutrophilic, Chronic - genetics; Leukemia, Neutrophilic, Chronic - pathology; Life Sciences; Male; Mutation; Pedigree; Receptors, Colony-Stimulating Factor - genetics; Signal Transduction
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2019003206

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. 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 Ca2+ 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.