title: Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients.
abstract: Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in essential thrombocythemia (ET) with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L, and CALR mutations, using whole-exome sequencing and next-generation sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, 1 homozygous SH2B3 mutation, 1 MPLS505N, 1 MPLW515R, and 2 MPLS204P mutations. In the remaining patients, 4 presented a clonal and 7 a polyclonal hematopoiesis, suggesting that certain triple-negative ETs are not MPNs. NGS on 26 additional triple-negative ETs detected only 1 MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN.
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Xénia
authors.initials: X
authors.lastname: Cabagnols
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Favale
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Kahia
authors.initials: K
authors.lastname: Messaoudi
authors.affiliation: de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; Ludwig Institute for Cancer Research, Signal Transduction & Molecular Hematology Unit, Brussels, Belgium;
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Defour
authors.affiliation: Service d'Hématologie, Centre Hospitalier Universitaire (CHU) Brest, Brest, France;
authors.forename: Jean Christophe
authors.initials: JC
authors.lastname: Ianotto
authors.affiliation: Laboratoire d'Hématologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Marzac
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Le Couédic
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.affiliation: de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; Ludwig Institute for Cancer Research, Signal Transduction & Molecular Hematology Unit, Brussels, Belgium;
authors.forename: Ilyas
authors.initials: I
authors.lastname: Chachoua
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Remi
authors.initials: R
authors.lastname: Favier
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: M'boyba Khadija
authors.initials: MK
authors.lastname: Diop
authors.affiliation: Laboratoire d'Hématologie, CHU Brest, Brest, France;
authors.forename: Valérie
authors.initials: V
authors.lastname: Ugo
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France; Laboratoire d'Hématologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France;
authors.forename: Nicole
authors.initials: N
authors.lastname: Casadevall
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France; Département de Génétique, Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie, Assistance Publique-Hôpitaux de Paris, Paris, France; and.
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.affiliation: de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; Ludwig Institute for Cancer Research, Signal Transduction & Molecular Hematology Unit, Brussels, Belgium;
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Bluteau
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.affiliation: INSERM, Unité Mixte de Recherche (UMR) 1170, Gustave Roussy, Villejuif, France; Université Paris-Saclay, UMR1170, Gustave Roussy, Villejuif, France; UMR1170, Gustave Roussy, Villejuif, France; Consultation d'Hématologie-Immunologie, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
mesh_terms: D019943:Amino Acid Substitution; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003062:Codon; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D016207:Cytokines / Q000494:pharmacology; D004252:DNA Mutational Analysis; D059472:Exome; D005838:Genotype; D006098:Granulocytes / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D009154:Mutation; D021381:Protein Transport; D053628:Receptors, Thrombopoietin / Q000235:genetics* / Q000378:metabolism; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000378:metabolism
chemical_list: D003062:Codon; D016207:Cytokines; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D053614:Janus Kinase 2