Journal
BLOOD
Volume 120, Issue 19, Pages 4006-4017Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-02-334722
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Funding
- Cancer Research Society, Canada
- Leukemia and Lymphoma Research United Kingdom
- Cambridge Stem Cell Center
- NIHR Cambridge Biomedical Research Center
- Cole Foundation
- University Clinic of Essen
- German Cancer fund
- CIHR [MOP-84328]
- Tier 1 Canada Research Chair
- Cancer Research Society (Canada)
- BBSRC [BB/I00050X/1] Funding Source: UKRI
- MRC [G0800784] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I00050X/1] Funding Source: researchfish
- Cancer Research UK [12765] Funding Source: researchfish
- Medical Research Council [G0800784, G0800784B] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0900729/1] Funding Source: researchfish
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The coding single nucleotide polymorphism GFI136N in the human gene growth factor independence 1 (GFI1) is present in 3%-7% of whites and increases the risk for acute myeloid leukemia (AML) by 60%. We show here that GFI136N, in contrast to GFI136S, lacks the ability to bind to the Gfi1 target gene that encodes the leukemia-associated transcription factor Hoxa9 and fails to initiate histone modifications that regulate HoxA9 expression. Consistent with this, AML patients heterozygous for the GFI136N variant show increased HOXA9 expression compared with normal controls. Using ChipSeq, we demonstrate that GFI136N specific epigenetic changes are also present in other genes involved in the development of AML. Moreover, granulomonocytic progenitors, a bone marrow subset from which AML can arise in humans and mice, show a proliferative expansion in the presence of the GFI136N variant. In addition, granulomonocytic progenitors carrying the GFI136N variant allele have altered gene expression patterns and differ in their ability to grow after transplantation. Finally, GFI136N can accelerate a K-RAS driven fatal myeloproliferative disease in mice. Our data suggest that the presence of a GFI136N variant allele induces a preleukemic state in myeloid precursors by deregulating the expression of Hoxa9 and other AML-related genes. (Blood. 2012;120(19):4006-4017)
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