title: Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis.
abstract: 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. Toward 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 natural killer (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 nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice was successful for as long as 12 weeks after transplantation, indicating that MPL W515 mutations were present in HSCs. Moreover, the 2 MPL mutations induced a spontaneous megakaryocytic growth in culture with an overall normal response to thrombopoietin (TPO). In contrast, erythroid progenitors remained EPO dependent. These results demonstrate that in PMF, the MPL W515L or K mutation induces a spontaneous megakaryocyte (MK) differentiation and occurs in a multipotent HSCs.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), U790, Université Paris XI, Institut Gustave Roussy, Villejuif, France.
authors: Ronan
authors: R
authors: Chaligné
authors: Chloé
authors: C
authors: James
authors: Carole
authors: C
authors: Tonetti
authors: Rodolphe
authors: R
authors: Besancenot
authors: Jean Pierre
authors: JP
authors: Le Couédic
authors: Fanny
authors: F
authors: Fava
authors: Fréderic
authors: F
authors: Mazurier
authors: Isabelle
authors: I
authors: Godin
authors: Karim
authors: K
authors: Maloum
authors: Frédéric
authors: F
authors: Larbret
authors: Yann
authors: Y
authors: Lécluse
authors: William
authors: W
authors: Vainchenker
authors: Stéphane
authors: S
authors: Giraudier
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017354:Point Mutation; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000473:pathology; D053628:Receptors, Thrombopoietin / Q000235:genetics* / Q000378:metabolism; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D018952:Antigens, CD34; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human