FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology

Karen K. Vo, Danuta J. Jarocha, Randolph B. Lyde, Vincent Hayes, Christopher S. Thom, Spencer K. Sullivan, Deborah L. French and Mortimer Poncz

Key points

  • Paris-Trousseau Syndrome is due solely to FLI1 hemizygous deletion with ETS1 levels being normal.

  • Elevated FLI1 levels in megakaryocytes do not interfere with and may enhance megakaryopoiesis.


Friend Leukemia Virus Integration 1 (FLI1), a critical transcription factor (TF) during megakaryocyte differentiation, is amongst genes hemizygously deleted in Jacobsen syndrome, resulting in a macrothrombocytopenia termed Paris-Trousseau syndrome (PTSx). Recently, heterozygote human FLI1 mutations have been ascribed to cause thrombocytopenia. We studied induced-pluripotent stem cell (iPSC)-derived megakaryocytes (iMegs) to better understand these clinical disorders, beginning with iPSCs generated from a PTSx patient and iPSCs from a control line with a targeted heterozygous FLI1 knockout (FLI1+/-). PTSx and FLI1+/- iMegs replicate many of the described megakaryocyte/platelet features including a decrease in iMeg yield and fewer platelets released per iMeg. Platelets released in vivo from infusion of these iMegs had poor half-lives and functionality. We noted that the closely-linked ETS Proto-Oncogene 1 (ETS1) is over-expressed in these FLI1-deficient iMegs, suggesting that FLI1 negatively regulates ETS1 in megakaryopoiesis. Finally, we examined whether FLI1 overexpression would affect megakaryopoiesis and thrombopoiesis. We found increased yield of non-injured, in vitro iMeg yield and increased in vivo yield, half-life and functionality of released platelets. These studies confirm FLI1 heterozygosity results in pleiotropic defects similar to those noted with other critical megakaryocyte-specific TFs; however, unlike those TFs, FLI1 overexpression improved yield and functionality.

  • Submitted February 28, 2017.
  • Accepted April 14, 2017.