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The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates K-RAS driven myeloproliferative disorder in mice.

Authors: Khandanpour, C  Krongold, J  Schutte, J  Bouwman, F  Vassen, L  Gaudreau, MC  Chen, R  Calero-Nieto, FJ  Diamanti, E  Hannah, R  Meyer, SE  Grimes, HL  Van der Reijden, BA  Jansen, JH  Patel, CV  Peeters, JK  Lowenberg, B  Duhrsen, U  Gottgens, B  Moroy, T 
Citation: Khandanpour C, etal., Blood. 2012 Nov 8;120(19):4006-17. doi: 10.1182/blood-2011-02-334722. Epub 2012 Aug 28.
Pubmed: (View Article at PubMed) PMID:22932805
DOI: Full-text: DOI:10.1182/blood-2011-02-334722

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.

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CRRD Object Information
CRRD ID: 11040453
Created: 2016-03-08
Species: All species
Last Modified: 2016-03-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.