Presence of atypical thrombopoietin receptor (MPL) mutations in triple negative essential thrombocythemia patients. - Université de Bretagne Occidentale Accéder directement au contenu
Article Dans Une Revue Blood Année : 2015

Presence of atypical thrombopoietin receptor (MPL) mutations in triple negative essential thrombocythemia patients.

Christophe Marzac
  • Fonction : Auteur
Jean Pierre Le Couédic
  • Fonction : Auteur
Ilyas Chachoua
  • Fonction : Auteur
M'Boyba Khadija Diop
  • Fonction : Auteur
Najet Debili
  • Fonction : Auteur
Hana Raslova
Stefan N Constantinescu
  • Fonction : Auteur
Olivier Bluteau
  • Fonction : Auteur

Résumé

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 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, one homozygous SH2B3 mutation, one MPLS505N, one MPLW515R and two MPLS204P mutations. In the remaining patients, four presented a clonal and seven a polyclonal hematopoiesis, suggesting that certain triple negative ETs are not MPNs. NGS on 26 additional triple negative ETs detected only one 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.

Dates et versions

hal-01258942 , version 1 (19-01-2016)

Identifiants

Citer

Xénia Cabagnols, Fabrizia Favale, Florence Pasquier, Kahia Messaoudi, Jean Philippe Defour, et al.. Presence of atypical thrombopoietin receptor (MPL) mutations in triple negative essential thrombocythemia patients.. Blood, 2015, 127, pp.333-342. ⟨10.1182/blood-2015-07-661983⟩. ⟨hal-01258942⟩
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