1. ¹INSERM, U790, Villejuif, France
2. ²Université Paris XI, Villejuif, France
3. ³Institut Gustave Roussy, Villejuif, France
4. ⁴Laboratoire d'hématologie, Hôpital Henri Mondor et Université Paris XII, AP-HP, Créteil, France
5. ⁵Université Poitiers et Unité d'hématologie, Poitiers, France
6. ⁶Laboratoire d'hématologie cellulaire et moléculaire, CHU Grenoble, Grenoble, France
7. ⁷Service d'hématologie clinique, Hôpital Avicenne et Université Paris XIII, AP-HP, Bobigny, France
8. ⁸Unité d'hématologie et de transplantation, Hôpital St Louis, AP-HP, Paris, France
9. ⁹UMR CNRS 6101, Service d'hématologie clinique, CHU Limoges, Limoges, France
10. ¹⁰INSERM U602, Hôpital Paul Brousse, et Université Paris-Sud, Hôpital Paul Brousse, Villejuif, France

Correspondence: Dr S Giraudier, Hematologie, INSERM U790, Institut Gustave Roussy, PR1, 39 rue Camille Desmoulins, Villejuif 94805, France. E-mails: sgiraudi@igr.fr and stephane.giraudier@hmn.aphp.fr

Received 24 April 2008; Accepted 5 May 2008; Published online 5 June 2008.

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.