New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition.

Ronan Chaligné; Carole Tonetti; Rodolphe Besancenot; Laurence Roy; Caroline Marty; Pascal Mossuz; Jean-Jacques Kiladjian; Gérard Socié; Dominique Bordessoule; Marie-Caroline Le Bousse-Kerdilès; William Vainchenker; Stéphane Giraudier

doi:10.1038/leu.2008.137

Journal articles

New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition.

Ronan Chaligné ^{1, 2} Carole Tonetti ³ Rodolphe Besancenot ^{1, 2} Laurence Roy ^{1, 2, 4, 5} Caroline Marty ^{1, 2} Pascal Mossuz ⁶ Jean-Jacques Kiladjian ⁷ Gérard Socié ⁸ Dominique Bordessoule ⁹ Marie-Caroline Le Bousse-Kerdilès ¹⁰ William Vainchenker ^{1, 2} Stéphane Giraudier ^{1, 2, 3, *}

* Corresponding author

1 U790 - Hematopoïese et cellules souches normales et pathologiques

2 IGR - Institut Gustave Roussy

3 Laboratoire d'hématologie

4 Unité d'hématologie

5 Université de Poitiers

6 DBPC - Laboratoire d'hématologie cellulaire et moléculaire

7 Service d'hématologie clinique [Avicenne]

8 Unité d'hématologie et de transplantation

9 PMRIL - Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations

10 Microenvironnement et Physiopathologie de la Differenciation

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 G(1)/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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Neurons and Cognition [q-bio.NC]

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https://www.hal.inserm.fr/inserm-00410485
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Submitted on : Friday, August 21, 2009 - 9:56:42 AM
Last modification on : Wednesday, October 14, 2020 - 3:58:43 AM

New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition.

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New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition.

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