FLT3-mediated p38-MAPK activation participates in the control of megakaryopoiesis in primary myelofibrosis

Christophe Desterke, Chrystele Bilhou-Nabéra, Bernadette Guerton, Christophe Martinaud, Carole Tonetti, Denis Clay, Paola Guglielmelli, Alessandro Vannucchi, Dominique Bordessoule, Hans Hasselbalch, Brigitte Dupriez, Nassima Benzoubir, Marie Françoise Bourgeade, Olivier Pierre-Louis, Vladimir Lazar, William Vainchenker, Annelise Bennaceur-Griscelli, Heinz Gisslinger, Stéphane Giraudier, Marie Caroline Le Bousse-Kerdilés

Publikation: Bidrag til tidsskriftArtikelForskningpeer review

Abstrakt

Primary myelofibrosis (PMF) is characterized by increased number of hematopoietic progenitors and a dysmegakaryopoiesis which supports the stromal reaction defining this disease. We showed that increased ligand (FL) levels in plasma, hematopoietic progenitors, and stromal cells from PMF patients were associated with upregulation of the cognate Flt3 receptor on megakaryocytic (MK) cells. This connection prompted us to study a functional role for the FL/Flt3 couple in PMF dysmegakaryopoiesis, as a route to reveal insights into pathobiology and therapy in this disease. Analysis of PMF CD34+ and MK cell transcriptomes revealed deregulation of the mitogen-activated protein kinase (MAPK) pathway along with Flt3 expression. In PMF patients, a higher proportion of circulating Flt3+CD34+CD41+ cells exhibited an increased MAPK effector phosphorylation independently of Jak 2V617F mutation. Activation of FL/Flt3 axis in PMF MK cell cultures, in response to FL, induced activation of the p38-MAPK cascade, which is known to be involved in inflammation, also increasing expression of its target genes (NFATC4, p53, AP-1, IL-8). Inhibiting Flt3 or MAPK or especially p38 by chemical, antibody, or silencing strategies restored megakaryopoiesis and reduced phosphorylation of Flt3 and p38 pathway effectors, confirming the involvement of Flt3 in PMF dysmegakaryopoiesis via p38 activation. In addition, in contrast to healthy donors,MKcells derived from PMF CD34+ cells exhibited an FL-induced migration that could be reversed by p38 inhibition. Taken together, our results implicate the FL/Flt3 ligand-receptor complex in PMF dysmegakaryopoiesis through persistent p38-MAPK activation, with implications for therapeutic prospects to correct altered megakaryopoiesis in an inflammatory context.

OriginalsprogEngelsk
Sider (fra-til)2901-2915
Antal sider15
TidsskriftCancer Research
Vol/bind71
Udgave nummer8
DOI
StatusUdgivet - 15 apr. 2011

Fingeraftryk Udforsk hvilke forskningsemner 'FLT3-mediated p38-MAPK activation participates in the control of megakaryopoiesis in primary myelofibrosis' indeholder.

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