Inherited transmission of the CSF3R T618I mutational hotspot in familial chronic neutrophilic leukemia - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Blood Année : 2019

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

Nicolas Duployez
Christophe Willekens
Alice Marceau-Renaut
Stéphane de Botton
Laurène Fenwarth
Thomas Boyer
Guillemette Huet
  • Fonction : Auteur
Olivier Nibourel
Christian Rose
  • Fonction : Auteur
Brigitte Nelken
Bruno Quesnel
Claude Preudhomme

Résumé

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.

Dates et versions

hal-04441297 , version 1 (06-02-2024)

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Citer

Nicolas Duployez, Christophe Willekens, Isabelle Plo, Alice Marceau-Renaut, Stéphane de Botton, et al.. Inherited transmission of the CSF3R T618I mutational hotspot in familial chronic neutrophilic leukemia. Blood, 2019, 134 (26), pp.2414-2416. ⟨10.1182/blood.2019003206⟩. ⟨hal-04441297⟩
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