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 ؋ 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. (Blood.

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

“…Initial experiments indicate that GFI136N has a different subnuclear localization than GFI136S and may act differently in the presence of the oncofusion protein AML-Eto in regulating target genes. 77 GFI136N is less efficient in inducing histone deacetylation and demethylation at the Hoxa9 locus than the more common GFI136S form.…”

“…41,56 Other studies show that loss of Gfi1 accelerates the development of a fatal myeloproliferative syndrome (MPS) in mice either in cooperation with an activated K-Ras gene or in the presence of constitutive Bcl-2 expression. 41,56 The only potential connection between GFI1 and AML is the finding that a human variant GFI1 allele, in which a coding single nucleotide polymorphism (rs34631763) causes a serine to arginine exchange at amino acid position 36, 77 occurs with a frequency of 0.04 in healthy white individuals but shows an increased frequency in AML patients. Hence, carriers of this variant allele have a 1.6-fold increased risk to develop AML.…”

“…Hence, carriers of this variant allele have a 1.6-fold increased risk to develop AML. 77 The presence of 1 GFI136N allele alone is insufficient to induce AML in mice but induces the expansion of GMPs and accelerates a K-Ras-induced myeloproliferative disease. 40 How GFI136N differs functionally from the more common GFI136S is not known and requires further investigation.…”

Gfi1 and Gfi1b: key regulators of hematopoiesis

“…Recently, a polymorphism in Gfi1 that predisposes to acute myeloid leukemia development in humans has been found. 62 This Gfi1 variant, which is characterized by the substitution of a serine by an asparagine at amino-acid position 36, does not affect its repressive properties, but does cause the protein to adopt an aberrant nuclear localization. The altered localization may imply that the variant form of Gfi1 is part of other protein complexes as compared with the common form of Gfi1.…”

Growth Factor Independence 1 Protects Hematopoietic Stem Cells Against Apoptosis but Also Prevents the Development of a Myeloproliferative-Like Disease

“…In addition, a Gfi1 variant is associated with AML and, neutropenia causing mutations of Gfi1 are associated with an elevated AML risk [37][38][39][40][41]. Moreover, Gfi1-deficient mice show expanded myeloid cell populations and up-regulated levels of Hoxa9.…”