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| Status |
Public on Dec 04, 2012 |
| Title |
The Growth factor independence 1 (GFI1) 36N variant predisposes to Acute Myeloid Leukemia (AML) by inducing epigenetic changes at the Hoxa9 locus |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
GFI136N is a coding Single Nucleotide Polymorphism (SNP) in the gene GFI1 that increases the risk for Acute myeloid leukemia (AML) by 60%. It is present in 3-5% of Caucasians and has a prevalence of 12% among AML patients. We generated knockin mice expressing either the human GFI136N variant or the more common GFI136S form and observed that GFI136N, in contrast to GFI136S, lacked the ability to bind to the Gfi1 target gene and leukemia associated transcription factor Hoxa9 in myeloid precursors and failed to initiate the histone modifications that regulate HoxA9 expression. Consistent with this, GFI136N heterozygous AML patients showed increased HOXA9 expression compared to control patients. In the knockin mice, granulo-monocytic pogenitors (GMPs), a bone marrow subset from which AML can arise, show a proliferative expansion in the presence of the GFI136N variant. Finally, the GFI136N variant increased colony formation and proliferation of myeloid precursors induced by the onco-fusion proteins MLL/AF9 or AML1/Eto9a and accelerated the onset of a KRAS-driven myelo-proliferative disease. Our data suggest that GFI136N predisposes to AML by deregulating the expression of Hoxa9, a locus highly relevant for AML, thereby inducing a pre-leukemic state in myeloid precursors that can give rise to AML.
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| Overall design |
3 samples (2 histone modifications, 1 transcription factor)
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| Contributor(s) |
Khandanpour C, Krongold J, Schütte J, Bouwman F, Vassen L, Gaudreau M, Chen R, Calero-Nieto F, Diamanti E, Hannah R, Meyer SE, Grimes LH, van der Reijden BA, Jansen JH, Patel CV, Peeters JK, Löwenberg B, Dührsen U, Göttgens B, Möröy T |
| Citation(s) |
22932805, 23410974 |
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| Submission date |
Aug 25, 2011 |
| Last update date |
May 15, 2019 |
| Contact name |
Judith Schütte |
| E-mail(s) |
js854@cam.ac.uk
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| Phone |
+441223336822
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| Organization name |
Cambridge Institue for Medical Research
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| Street address |
Hills Road
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| City |
Cambridge |
| ZIP/Postal code |
CB2 0XY |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL9250 |
Illumina Genome Analyzer II (Mus musculus) |
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| Samples (3) |
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| Relations |
| SRA |
SRP007942 |
| BioProject |
PRJNA145405 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE31657_RAW.tar |
3.0 Gb |
(http)(custom) |
TAR (of BW, SAM) |
SRA Run Selector |
| Processed data provided as supplementary file |
| Raw data are available in SRA |
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