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

Content Provider	PubMed Central
Author	Cyrus, Khandanpour Thiede, Christian Valk, Peter J. M. Sharif-askari, Ehssan Holger, Nückel Lohmann, Dietmar Horsthemke, Bernhard Siffert, Winfried Neubauer, Andreas Grzeschik, Karl-heinz Bloomfield, Clara D. Marcucci, Guido Kati, Maharry Slovak, Marilyn L. Reijden, Bert A. Van Der Jansen, Joop H. Schackert, Hans K. Afshar, Khashayar Schnittger, Susanne Peeters, Justine K. Frank, Kroschinsky Ehninger, Gerhard Lowenberg, Bob Ulrich, Dührsen Tarik, Möröy
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 (GFI136N ) is associated with acute myeloid leukemia (AML) in white subjects with an odds ratio of 1.6 (P < 8 × 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 GFI136S form in the nucleus and inhibits its repressor activity. However, the variant GFI136N protein has a different subnuclear localization than GFI136S. As a consequence, AML1/ETO does not colocalize with GFI136N 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 GFI136N variant form exhibits distinct biochemical features that may confer a predisposition to AML.
Related Links	http://dx.doi.org/10.1182/blood-2009-08-239822
Ending Page	2472
Page Count	11
Starting Page	2462
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	12
Volume Number	115
Language	English
Publisher	American Society of Hematology
Publisher Date	2010-03-25
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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