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Exp Hematol. 2016 Aug;44(8):713-726.e14. doi: 10.1016/j.exphem.2016.05.004. Epub 2016 May 20.

Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML.

Author information

1
Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
2
Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada.
3
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH.
4
Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada; Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada.
5
Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
6
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
7
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
8
Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada; Department of Hematology and Oncology, University Hospital Düsseldorf, Düsseldorf, Germany; Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada. Electronic address: Tarik.Moroy@ircm.qc.ca.
9
Department of Hematology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Electronic address: cyrus.khandanpour@uk-essen.de.

Abstract

Epigenetic changes can contribute to development of acute myeloid leukemia (AML), a malignant disease of the bone marrow. A single-nucleotide polymorphism of transcription factor growth factor independence 1 (GFI1) generates a protein with an asparagine at position 36 (GFI1(36N)) instead of a serine at position 36 (GFI1(36S)), which is associated with de novo AML in humans. However, how GFI1(36N) predisposes to AML is poorly understood. To explore the mechanism, we used knock-in mouse strains expressing GFI1(36N) or GFI1(36S). Presence of GFI1(36N) shortened the latency and increased the incidence of AML in different murine models of myelodysplastic syndrome/AML. On a molecular level, GFI1(36N) induced genomewide epigenetic changes, leading to expression of AML-associated genes. On a therapeutic level, use of histone acetyltransferase inhibitors specifically impeded growth of GFI1(36N)-expressing human and murine AML cells in vitro and in vivo. These results establish, as a proof of principle, how epigenetic changes in GFI1(36N)-induced AML can be targeted.

PMID:
27216773
DOI:
10.1016/j.exphem.2016.05.004
[Indexed for MEDLINE]
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