An incomplete trafficking defect to the cell-surface leads to paradoxical thrombocytosis for human and murine MPL P106L
Fabrizia Favale, Kahia Messaoudi, Leila N Varghese, Siham Boukour, Christian Pecquet, Vitalina Gryshkova, Jean Philippe Defour, Roxana-Irina Albu, Olivier Bluteau, Paola Ballerini, Guy Leverger, Isabelle Plo, Najet Debili, Hana Raslova, Remi Favier, Stefan N Constantinescu, William Vainchenker
BLOOD | AMER SOC HEMATOLOGY | Published : 2016
The mechanisms behind the hereditary thrombocytosis induced by the thrombopoietin (THPO) receptor MPL P106L mutant remain unknown. A complete trafficking defect to the cell surface has been reported, suggesting either weak constitutive activity or nonconventional THPO-dependent mechanisms. Here, we report that the thrombocytosis phenotype induced by MPL P106L belongs to the paradoxical group, where low MPL levels on platelets and mature megakaryocytes (MKs) lead to high serum THPO levels, whereas weak but not absent MPL cell-surface localization in earlier MK progenitors allows response to THPO by signaling and amplification of the platelet lineage. MK progenitors from patients showed no spo..View full abstract
Awarded by Action de Recherche Concertee (ARC) of the University catholique de Louvain
Awarded by Pole d'attraction interuniversitaires Programs
Support is acknowledged to S.N.C. from Ludwig Institute for Cancer Research, Fund for Scientific Research-Fund for Scientific Research, Salus Sanguinis Foundation, the Action de Recherche Concertee (ARC) project ARC10/15-027 of the University catholique de Louvain, the Fondation contre le Cancer, the Pole d'attraction interuniversitaires Programs BCHM61B5, and Belgian Medical Genetics Initiative. J.P.D., R.-I.A., and V.G. were supported by Fund for Research Training in Industry and Agriculture, Televie, and Belgian Federal Science Policy Office Interuniversity Attraction Poles postdoctoral fellowship. L.N.V. was supported by a Haas-Teichen fellowship and a postdoctoral fellowship at the de Duve Institute from the Maurange Fund, Belgium. This work was supported by grants from the Agence Nationale pour la Recherche (Thrombocytosis [W.V.]), the Ligue Nationale contre le Cancer (Equipe labellisee), and the Fondation Laurette Fugain (W.V.). F. F. was supported by the INSERM (Poste d'accueil) and the ARC Foundation, and M.K. was supported by the University Paris-Diderot.