TY - JOUR
T1 - FLT3-mediated p38-MAPK activation participates in the control of megakaryopoiesis in primary myelofibrosis
AU - Desterke, Christophe
AU - Bilhou-Nabéra, Chrystele
AU - Guerton, Bernadette
AU - Martinaud, Christophe
AU - Tonetti, Carole
AU - Clay, Denis
AU - Guglielmelli, Paola
AU - Vannucchi, Alessandro
AU - Bordessoule, Dominique
AU - Hasselbalch, Hans
AU - Dupriez, Brigitte
AU - Benzoubir, Nassima
AU - Bourgeade, Marie Françoise
AU - Pierre-Louis, Olivier
AU - Lazar, Vladimir
AU - Vainchenker, William
AU - Bennaceur-Griscelli, Annelise
AU - Gisslinger, Heinz
AU - Giraudier, Stéphane
AU - Le Bousse-Kerdilés, Marie Caroline
PY - 2011/4/15
Y1 - 2011/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79954595370&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-1731
DO - 10.1158/0008-5472.CAN-10-1731
M3 - Article
C2 - 21487043
AN - SCOPUS:79954595370
VL - 71
SP - 2901
EP - 2915
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 8
ER -