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GFI1 as a novel prognostic and therapeutic factor for AML/MDS

GFI1 as a novel prognostic and therapeutic factor for AML/MDS

Authors :
Hönes, J M
Botezatu, L
Helness, A
Vadnais, C
Vassen, L
Robert, F
Hergenhan, S M
Thivakaran, A
Schütte, J
Al-Matary, Y S
Lams, R F
Fraszscak, J
Makishima, H
Radivoyevitch, T
Przychodzen, B
da Conceição Castro, S V
Görgens, A
Giebel, B
Klein-Hitpass, L
Lennartz, K
Heuser, M
Thiede, C
Ehninger, G
Dührsen, U
Maciejewski, J P
Möröy, T
Khandanpour, C
Source :
Leukemia; June 2016, Vol. 30 Issue: 6 p1237-1245, 9p
Publication Year :
2016

Abstract

Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1expression. Leukemic cells from animals that express low levels of GFI1show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KDmice and from AML patients with low GFI1levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.

Details

Language :
English
ISSN :
08876924 and 14765551
Volume :
30
Issue :
6
Database :
Supplemental Index
Journal :
Leukemia
Publication Type :
Periodical
Accession number :
ejs39274854
Full Text :
https://doi.org/10.1038/leu.2016.11