CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Blood Année : 2021

CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag

Francesca Basso-Valentina
  • Fonction : Auteur
Gabriel Levy
  • Fonction : Auteur
Leila Varghese
  • Fonction : Auteur
Myriam Oufadem
Benedicte Neven
  • Fonction : Auteur
Charlotte Boussard
  • Fonction : Auteur
Nathalie Balayn
  • Fonction : Auteur
William Vainchenker
Isabelle Plo
Paola Ballerini
  • Fonction : Auteur
Stefan Constantinescu
  • Fonction : Auteur
Remi Favier
  • Fonction : Auteur
Hana Raslova

Résumé

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 limited signaling with TPO stimulation, leading to survival and reduced proliferation of cells. Overexpression of a myeloproliferative neoplasm–associated calreticulin (CALR) mutant did not rescue trafficking of MPLR464G to the cell surface and did not induce constitutive signaling. However, it unexpectedly restored a normal response to eltrombopag (ELT), but not to TPO. This effect was only partially mimicked by the purified recombinant CALR mutant protein. Finally, the endogenous CALR mutant was able to restore the megakaryocyte differentiation of patient CD34+ cells carrying MPLR464G in response to ELT.

Dates et versions

hal-04429984 , version 1 (31-01-2024)

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Citer

Francesca Basso-Valentina, Gabriel Levy, Leila Varghese, Myriam Oufadem, Benedicte Neven, et al.. CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag. Blood, 2021, 138 (6), pp.480-485. ⟨10.1182/blood.2020010567⟩. ⟨hal-04429984⟩
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