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Oncogenic activation of MPL/thrombopoietin receptor by 17 mutations at W515: implications for myeloproliferative neoplasms

Leukemia volume 30, pages 1214–1216 (2016)Cite this article

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Philadelphia negative myeloproliferative neoplasms (MPNs) include polycythemia vera, essential thrombocythemia (ET) and primary myelofibrosis (PMF). Those MPNs are clonal diseases for which the phenotype is almost driven by exon-specific somatic mutations in three genes: JAK2 exon14, MPL exon10 and CALR exon9.

MPNs lacking those specific driver mutations are commonly called ‘triple negatives’, which amount to 15% of ET and PMF and appear to share with phenotypic drivers the ability to activate the JAK/STAT pathway.1 Beside JAK2 and STATs, MPL/TpoR is a central player in the pathogenesis of MPN being essential for developing a full JAK2 V617F disease in mice.2 However, the receptor itself can suffer from pathological activating mutations within exon10. Exon10 covers roughly the transmembrane domain (TMD) of TpoR and starts at Trp491 (exoplasmic TMD boundary) to end shortly after Trp515 (cytosolic TMD boundary). Those two tryptophans are predicted to be on the same face of the TMD helix and are capping the TMD helix in the membrane bilayer. Trp515 is found in an amphipathic and helical motif ‘RWQFP’ that prevents activation of TpoR.3 Trp515 itself controls dimerization and activation of the receptor.4 W515S,5 W515L,6 W515K,7 W515A,8 W515R9 and W515G10 were shown to be present in a subset of MPN patients (nearby 4% ET and 8% PMF in large cohorts), or in autonomous cell lines but have never been found in polycythemia vera or other myeloid diseases.7, 11, 12 W515L/K mutations are the most prevalent mutations that activate the receptor and recapitulate an ET/PMF phenotype with marked thrombocytosis in murine bone marrow transplant assays.6, 8 Besides missense mutations, rare deletions and insertions around W515 are found in MPN patients.10, 12

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Acknowledgements

We thank Prof. Steven O. Smith for structural biology insights and Nicolas Dauguet for expert cell sorting. We are grateful for generous support to SNC from the Ludwig Institute for Cancer Research, FRS-FNRS, Salus Sanguinis Foundation, the Action de Recherche Concertée project ARC10/15–027 of the University catholique de Louvain, the Fondation contre le Cancer, the PAI Programs BCHM61B5 and Belgian Medical Genetics Initiative (BeMG), Belgium. JPD and IC were supported by FRIA and Télévie-FRS-FNRS PhD fellowships, Belgium. JPD was also supported by the Cliniques universitaires St Luc, Brussels, Belgium.

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  1. Cell Signaling Pole, Signal Transduction and Molecular Hematology, Ludwig Institute for Cancer Research and de Duve Institute, Université catholique de Louvain, Brussels, Belgium

    J-P Defour, I Chachoua, C Pecquet & S N Constantinescu

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Correspondence to S N Constantinescu.

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Defour, JP., Chachoua, I., Pecquet, C. et al. Oncogenic activation of MPL/thrombopoietin receptor by 17 mutations at W515: implications for myeloproliferative neoplasms. Leukemia 30, 1214–1216 (2016). https://doi.org/10.1038/leu.2015.271

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