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Title: Epigenetic therapy as a novel approach for GFI136N-associated AML      
keywords:
Epigenomics
ID:
PRJNA309396
description:
Acute myeloid leukemia (AML) is characterized by accumulation of myeloid blast cells in the bone marrow. Despite all efforts, prognosis of AML patients remains poor, warranting new therapeutic approaches. A single nucleotide polymorphism of growth factor independence 1 (GFI1), a hematopoietic transcription factor, generates a protein with an asparagine (GFI136N) instead of a serine at position 36 (GFI136S), which we have previously reported to be associated with de novo AML in humans. Using knock-in mouse strains, in which the endogenous murine Gfi1 coding sequences are substituted by human GFI136N or GFI136S, we found that GFI136N shortened latency and increased incidence of AML in three different, well-established murine models of AML. On a molecular level, the presence of GFI136N was associated with increased acetylation of histone H3 at lysine 9 (H3K9) at Gfi1 target genes in both murine and human samples, contributing to AML development. Since in GFI136N containing leukemic cells Gfi1 target genes have hyperacetylated H3K9, the treatment strategy currently used with histone deacetylases inhibitors (HDACis) might not be beneficial. We show that treatment with an HDACi impeded growth of murine and human cells homozygous for GFI136S, but had a limited effect on cells expressing GFI136N. In contrast, treatment with a histone acetyltransferase inhibitor (HATi) specifically targeted GFI136N-expressing malignant cells while sparing non-malignant cells. These results establish, as a proof of principle, how epigenetic changes in GFI136N-induced AML can be exploited to treat AML and implicate HATi as a new, more effective potential therapeutic strategy for GFI136N AML patients. Overall design: one sample per genotype has been sequenced
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA309396
authentication:
none
authorization:
none
ID:
pmid:27216773
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject