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

Cancer Res. 2011 Apr 15;71(8):2901-15. doi: 10.1158/0008-5472.CAN-10-1731. Epub 2011 Apr 12.


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 Jak2(V617F) 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, MK cells 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD34 / biosynthesis
  • Enzyme Activation
  • Hematopoietic Stem Cells / enzymology
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukocytes, Mononuclear / enzymology
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • MAP Kinase Signaling System
  • Megakaryocytes / enzymology
  • Megakaryocytes / metabolism*
  • Megakaryocytes / pathology
  • Membrane Proteins / blood
  • Membrane Proteins / metabolism
  • Membrane Proteins / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Primary Myelofibrosis / blood
  • Primary Myelofibrosis / enzymology
  • Primary Myelofibrosis / metabolism*
  • Stromal Cells / enzymology
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • fms-Like Tyrosine Kinase 3 / biosynthesis
  • fms-Like Tyrosine Kinase 3 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Antigens, CD34
  • Membrane Proteins
  • flt3 ligand protein
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases