title: FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U 362, Villejuif, France.
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
authors.forename: Emiko
authors.initials: E
authors.lastname: Komura
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Le Couédic
authors.forename: Frederic
authors.initials: F
authors.lastname: Larbret
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: Jean
authors.initials: J
authors.lastname: Feunteun
authors.forename: Olivier
authors.initials: O
authors.lastname: Danos
authors.forename: Olivier
authors.initials: O
authors.lastname: Albagli
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Rémi
authors.initials: R
authors.lastname: Favier
mesh_terms: 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
chemical_list: 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