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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3735-3743.
Prepublished online as a Blood First Edition Paper on August 20, 2007; DOI 10.1182/blood-2007-05-089003.
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Submitted May 7, 2007
Accepted August 6, 2007
Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis
Ronan Chaligne, Chloe James, Carole Tonetti, Rodolphe Besancenot, Jean Pierre Le Couedic, Fanny Fava, Frederic Mazurier, Isabelle Godin, Karim Maloum, Frederic Larbret, Yann Lecluse, William Vainchenker, and Stephane Giraudier*
INSERM, U790, Universite Paris XI, Institut gustave Roussy, Villejuif, France
INSERM, U876, Universite Bordeaux II, Bordeaux, France
AP-HP, Laboratoire d'Hematologie, Hopital Henri Mondor and Universite Paris XII, Creteil, France
AP-HP, Laboratoire d'Hematologie, Hopital La Pitie-Salpetriere, Paris, France
* Corresponding author; email: stephane.giraudier{at}hmn.aphp.fr.
The MPL (W515L and W515K) mutations have been detected in granulocytes of patients suffering from certain types of Primitive Myelofibrosis (PMF). It is still unknown whether this molecular event is also present in lymphoid cells and therefore potentially at the Hematopoietic stem cell (HSC) level. Towards this goal, we conducted MPL genotyping of mature myeloid and lymphoid cells and of lymphoid/myeloid progenitors isolated from PMF patients carrying the W515 mutations. We detected both MPL mutations in granulocytes, monocytes and platelets as well as NK cells but not in T cells. B/NK/Myeloid and/or NK/Myeloid CD34+CD38- derived clones were found to carry the mutations. Long term reconstitution of MPL W515 CD34+ cells in NOD/SCID mice was successful as long as 12 weeks post-transplantation indicating that MPL W515 mutations were present in HSC. Moreover, the two MPL mutations induced a spontaneous megakaryocytic growth in culture with an overall normal response to TPO. In contrast, erythroid progenitors remained EPO-dependent. These results demonstrate that in PMF, the MPL W515L or K mutation induces a spontaneous MK differentiation and occurs in a multipotent HSC.
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