CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag
| Autor: | Hana Raslova, Isabelle Plo, Paola Ballerini, Rémi Favier, Caroline Marty, Leila N. Varghese, Myriam Oufadem, Gabriel Levy, Nathalie Balayn, Francesca Basso-Valentina, Charlotte Boussard, William Vainchenker, Bénédicte Neven, Stefan N. Constantinescu |
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| Přispěvatelé: | UCL - SSS/DDUV/SIGN - Cell signalling, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Megakaryocyte differentiation Immunology Mutant Eltrombopag Mutation Missense Biology medicine.disease_cause Biochemistry Benzoates chemistry.chemical_compound Mutant protein medicine Congenital Bone Marrow Failure Syndromes Humans Child Thrombopoietin Mutation Homozygote Infant Cell Biology Hematology medicine.disease Molecular biology Thrombocytopenia HEK293 Cells Hydrazines chemistry Amino Acid Substitution Child Preschool biology.protein Congenital amegakaryocytic thrombocytopenia Pyrazoles Female Calreticulin Receptors Thrombopoietin |
| Zdroj: | Blood, Vol. 138, no. 6, p. 480-485 (2021) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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