Abstract
MPL (or thrombopoietin receptor, TPO-R) 515 mutations have recently been described in 5–10% of primitive myelofibrosis (PMF) cases as decisive oncogenic events capable of triggering the disease. Here we report additional mutations located in exon 10 of MPL in PMF patients. We investigated whether these new mutations also lead to cell transformation. MPL exon 10 was systematically sequenced in 100 PMF patients. Seven different mutations were found in eight patients. We introduced each MPL mutant in Ba/F3 cells to determine whether they correspond to gain-of-function mutations. Only MPL W515 mutations induced (1) Ba/F3 proliferation independently of growth factors, (2) tumorigenesis in nude mice, (3) spontaneous activation of JAK/STAT, RAS/MAPK and PI3K transduction pathways and (4) increased S phase of cell cycle. Similar to all other myeloproliferative disorder oncogenic events identified to date, these results demonstrate that only the detected MPL W515 mutations trigger spontaneous MPL activation leading to a G1/S transition activation. The other mutations are devoid of significant transforming activity but may synergize with JAK2 V617F or other not yet characterized molecular events.
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Acknowledgements
We thank Caroline Lefebvre for helpful discussions and improving the eEnglish paper. This work was supported by grants from Institut National de la Santé et la Recherche Médicale (INSERM) and La Ligue Nationale contre le Cancer (équipe labellisée 2004 and 2007). RC is supported by the Research Ministry. Author's contributions: RC, CT, RB, SG performed cellular experiments. SG, WV, PM, LR, JJK and MCLBK contributed to the recruitment of the patients. RC, WV, LR and SG designed the study and analyzed the data. RC, CM, WV and SG wrote the paper.
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Chaligné, R., Tonetti, C., Besancenot, R. et al. New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition. Leukemia 22, 1557–1566 (2008). https://doi.org/10.1038/leu.2008.137
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DOI: https://doi.org/10.1038/leu.2008.137
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