A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia.
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.
Khandanpour
Cyrus
C
Institut de Recherches Cliniques de Montréal (IRCM) and Département de Microbiologie et Immunologie, Université de Montréal, Montréal, QC H2W 1R7, Canada.
Thiede
Christian
C
Valk
Peter J M
PJ
Sharif-Askari
Ehssan
E
Nückel
Holger
H
Lohmann
Dietmar
D
Horsthemke
Bernhard
B
Siffert
Winfried
W
Neubauer
Andreas
A
Grzeschik
Karl-Heinz
KH
Bloomfield
Clara D
CD
Marcucci
Guido
G
Maharry
Kati
K
Slovak
Marilyn L
ML
van der Reijden
Bert A
BA
Jansen
Joop H
JH
Schackert
Hans K
HK
Afshar
Khashayar
K
Schnittger
Susanne
S
Peeters
Justine K
JK
Kroschinsky
Frank
F
Ehninger
Gerhard
G
Lowenberg
Bob
B
Dührsen
Ulrich
U
Möröy
Tarik
T
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
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