FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia.
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.
Raslova
Hana
H
Institut National de la Santé et de la Recherche Médicale U 362, Villejuif, France.
Komura
Emiko
E
Le Couédic
Jean Pierre
JP
Larbret
Frederic
F
Debili
Najet
N
Feunteun
Jean
J
Danos
Olivier
O
Albagli
Olivier
O
Vainchenker
William
W
Favier
Rémi
R
D015703:Antigens, CD / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D015703:Antigens, CD; D017931:DNA Primers; D004268:DNA-Binding Proteins; C078433:FLI1 protein, human; D051789:Proto-Oncogene Protein c-fli-1; D011994:Recombinant Proteins; D015534:Trans-Activators