MPL mutations in essential thrombocythemia uncover a common path of activation with eltrombopag dependent on W491
Gabriel Levy, Serge Carillo, Benjamin Papoular, Bruno Cassinat, Jean-Marc Zini, Emilie Leroy, Leila N Varghese, Ilyas Chachoua, Jean-Philippe Defour, Steven O Smith, Stefan N Constantinescu
BLOOD | AMER SOC HEMATOLOGY | Published : 2020
Mutations in the MPL gene encoding the human thrombopoietin receptor (TpoR) drive sporadic and familial essential thrombocythemias (ETs). We identified 2 ET patients harboring double mutations in cis in MPL, namely, L498W-H499C and H499Y-S505N. Using biochemical and signaling assays along with partial saturation mutagenesis, we showed that L498W is an activating mutation potentiated by H499C and that H499C and H499Y enhance the activity of the canonical S505N mutation. L498W and H499C can activate a truncated TpoR mutant, which lacks the extracellular domain, indicating these mutations act on the transmembrane (TM) cytosolic domain. Using a protein complementation assay, we showed that L498W..View full abstract
Awarded by Action de Recherche Concertee Projects
G.L. was supported by a fellowship awarded from the Foundation "Les Avions de Sebastien." L.N.V. has received support from the de Duve Institute Maurange Funds postdoctoral fellowship and the MOVE-IN Louvain fellowship. S.N.C. is Honorary Research Director at Fonds de la Recherche Scientifique (FRS-FNRS) Belgium and has received funds from Ludwig Institute for Cancer Research, Fondation contre le Cancer, Salus Sanguinis, and Action de Recherche Concertee Projects 16/21-073 and WelBio F 44/8/5-MCF/UIG-10955.