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

作者：Khandanpour Cyrus; Thiede Christian; Valk Peter J M; Sharif Askari Ehssan; Nueckel Holger; Lohmann Dietmar; Horsthemke Bernhard; Siffert Winfried; Neubauer Andreas; Grzeschik Karl Heinz; Bloomfield Clara D; Marcucci Guido; Maharry Kati; Slovak Marilyn L; van der Reijden Bert A; Jansen Joop H; Schackert Hans K; Afshar Khashayar; Schnittger Susanne; Peeters Justine K; Kroschinsky Frank; Ehninger Gerhard; Lowenberg Bob; Duehrsen Ulrich; Moroy Tarik^*

来源：Blood, 2010, 115(12): 2462-2472.

DOI：10.1182/blood-2009-08-239822

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 GFI136N 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. 2010;115:2462-2472)

• 出版日期2010-3-25