RGD Reference Report - A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia. - Rat Genome Database

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A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia.

Authors: Khandanpour, C  Thiede, C  Valk, PJ  Sharif-Askari, E  Nuckel, H  Lohmann, D  Horsthemke, B  Siffert, W  Neubauer, A  Grzeschik, KH  Bloomfield, CD  Marcucci, G  Maharry, K  Slovak, ML  Van der Reijden, BA  Jansen, JH  Schackert, HK  Afshar, K  Schnittger, S  Peeters, JK  Kroschinsky, F  Ehninger, G  Lowenberg, B  Duhrsen, U  Moroy, T 
Citation: Khandanpour C, etal., Blood. 2010 Mar 25;115(12):2462-72. doi: 10.1182/blood-2009-08-239822. Epub 2010 Jan 14.
RGD ID: 11040450
Pubmed: PMID:20075157   (View Abstract at PubMed)
PMCID: PMC2919174   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2009-08-239822   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GFI1Humanacute myeloid leukemia susceptibilityIAGP DNA:SNP:cds:c.107G>A(rs34631763)(human)RGD 
Gfi1Ratacute myeloid leukemia susceptibilityISOGFI1 (Homo sapiens)DNA:SNP:cds:c.107G>A(rs34631763)(human)RGD 
Gfi1Mouseacute myeloid leukemia susceptibilityISOGFI1 (Homo sapiens)DNA:SNP:cds:c.107G>A(rs34631763)(human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gfi1  (growth factor independent 1 transcriptional repressor)

Genes (Mus musculus)
Gfi1  (growth factor independent 1 transcription repressor)

Genes (Homo sapiens)
GFI1  (growth factor independent 1 transcriptional repressor)


Additional Information