FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia

J Clin Invest. 2004 Jul;114(1):77-84. doi: 10.1172/JCI21197.

Abstract

Paris-Trousseau syndrome (PTS; also known as Jacobsen syndrome) is characterized by several congenital anomalies including a dysmegakaryopoiesis with two morphologically distinct populations of megakaryocytes (MKs). PTS patients harbor deletions on the long arm of chromosome 11, including the FLI1 gene, which encodes a transcription factor essential for megakaryopoiesis. We show here that lentivirus-mediated overexpression of FLI1 in patient CD34(+) cells restores the megakaryopoiesis in vitro, indicating that FLI1 hemizygous deletion contributes to the PTS hematopoietic defects. FISH analysis on pre-mRNA and single-cell RT-PCR revealed that FLI1 expression is mainly monoallelic in CD41(+)CD42(-) progenitors, while it is predominantly biallelic in the other stages of megakaryopoiesis. In PTS cells, the hemizygous deletion of FLI1 generates a subpopulation of CD41(+)CD42(-) cells completely lacking FLI1 transcription. We propose that the absence of FLI1 expression in these CD41(+)CD42(-) cells might prevent their differentiation, which could explain the segregation of the PTS MKs into two subpopulations: one normal and one composed of small immature MKs undergoing a massive lysis, presumably originating from either FLI1(+) or FLI1(-) CD41(+)CD42(-) cells, respectively. Thus, we point to the role of transient monoallelic expression of a gene essential for differentiation in the genesis of human haploinsufficiency-associated disease and suggest that such a mechanism may be involved in the pathogenesis of other congenital or acquired genetic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics
  • Base Sequence
  • Cell Line
  • DNA Primers
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Flow Cytometry
  • Gene Deletion*
  • Humans
  • Intellectual Disability / genetics
  • Proto-Oncogene Protein c-fli-1
  • Recombinant Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Syndrome
  • Thrombocytopenia / blood
  • Thrombocytopenia / genetics*
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transfection

Substances

  • Antigens, CD
  • DNA Primers
  • DNA-Binding Proteins
  • FLI1 protein, human
  • Proto-Oncogene Protein c-fli-1
  • Recombinant Proteins
  • Trans-Activators