title: A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia.
abstract: The GFI1 gene encodes a transcriptional repressor, which regulates myeloid differentiation. In the mouse, Gfi1 deficiency causes neutropenia and an accumulation of granulomonocytic precursor cells that is reminiscent of a myelodysplastic syndrome. We report here that a variant allele of GFI1 (GFI1(36N)) is associated with acute myeloid leukemia (AML) in white subjects with an odds ratio of 1.6 (P < 8 x 10(-5)). The GFI1(36N) variant occurred in 1806 AML patients with an allele frequency of 0.055 compared with 0.035 in 1691 healthy control patients in 2 independent cohorts. We observed that both GFI1 variants maintain the same activity as transcriptional repressors but differ in their regulation by the AML1/ETO (RUNX1/RUNX1T1) fusion protein produced in AML patients with a t(8;21) translocation. AML1/ETO interacts and colocalizes with the more common GFI1(36S) form in the nucleus and inhibits its repressor activity. However, the variant GFI1(36N) protein has a different subnuclear localization than GFI1(36S). As a consequence, AML1/ETO does not colocalize with GFI1(36N) and is unable to inhibit its repressor activity. We conclude that both variants of GFI1 differ in their ability to be regulated by interacting proteins and that the GFI1(36N) variant form exhibits distinct biochemical features that may confer a predisposition to AML.
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM) and Département de Microbiologie et Immunologie, Université de Montréal, Montréal, QC H2W 1R7, Canada.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Khandanpour
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Ehssan
authors.initials: E
authors.lastname: Sharif-Askari
authors.forename: Holger
authors.initials: H
authors.lastname: Nückel
authors.forename: Dietmar
authors.initials: D
authors.lastname: Lohmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Horsthemke
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Grzeschik
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Slovak
authors.forename: Bert A
authors.initials: BA
authors.lastname: van der Reijden
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.forename: Khashayar
authors.initials: K
authors.lastname: Afshar
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Justine K
authors.initials: JK
authors.lastname: Peeters
authors.forename: Frank
authors.initials: F
authors.lastname: Kroschinsky
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Bob
authors.initials: B
authors.lastname: Lowenberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dührsen
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006367:HeLa Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors