Journal article
CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag
F Basso-Valentina, G Levy, LN Varghese, M Oufadem, B Neven, C Boussard, N Balayn, C Marty, W Vainchenker, I Plo, P Ballerini, SN Constantinescu, R Favier, H Raslova
Blood | AMER SOC HEMATOLOGY | Published : 2021
Abstract
Congenital amegakaryocytic thrombocytopenia (CAMT) is a severe inherited thrombocytopenia due to loss-of-function mutations affecting the thrombopoietin (TPO) receptor, MPL. Here, we report a new homozygous MPL variant responsible for CAMT in 1 consanguineous family. The propositus and her sister presented with severe thrombocytopenia associated with mild anemia. Next-generation sequencing revealed the presence of a homozygous MPLR464G mutation resulting in a weak cell-surface expression of the receptor in platelets. In cell lines, we observed a defect in MPLR464G maturation associated with its retention in the endoplasmic reticulum. The low cell-surface expression of MPLR464G induced very l..
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Awarded by Ludwig Institute for Cancer Research
Funding Acknowledgements
The authors thank the patients who participated in this study; M.C. Alessi, who coordinated the "Centre de Reference des Pathologies Plaquettaire" (Paris, France); and P. Rameau and C. Catelain from the Imaging and Cytometry Platform (Plate-Forme Imagerie et Cytometrie), Unite Mixte de Service Analyse Moleculaire, Modelisation et Imagerie de la aladie Cancereuse (PFIC, UMS AMMICA), Gustave Roussy Villejuif, France for their expertise in cytometry. F.B.-V. was supported by the Universite Sorbonne Paris Cite/Universite Paris Diderot and French Society of Hematology. The work of H.R.'s team is supported by the Ligue Nationale contre le Cancer (Equipe Labellisee 2016 and 2019 [H.R.]) and Institut Naitonal du Cancer Institut Naitonal du Cancer (INCa PLBIO); 2015, 2017, and 2018) (I.P.). S.C. was supported by funding from Ludwig Institute for Cancer Research, Fondation contre le Cancer of Belgium, Salus Sanguinis Foundation (Bruxelles, Belgium), and Fondation "Les Avions de Sebastien", Projects Action de Recherche Concertee 16/21-073 and WelBio F 44/8/5 -MCF/UIG -10955, is acknowledged.