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Haematologica. 2018 Apr;103(4):614-625. doi: 10.3324/haematol.2017.167288. Epub 2018 Jan 11.

Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome.

Author information

1
Department of Haematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
2
Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
3
Department of Haematology, Haemostaseology, Oncology, and Stem Cell Transplantation, Medical University of Hannover, Germany.
4
Institute for Cell Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
5
Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
6
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
7
Department of Haematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany cyrus.khandanpour@uk-essen.de.
8
Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Germany.

Abstract

Differentiation of hematopoietic stem cells is regulated by a concert of different transcription factors. Disturbed transcription factor function can be the basis of (pre)malignancies such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth factor independence 1b (Gfi1b) is a repressing transcription factor regulating quiescence of hematopoietic stem cells and differentiation of erythrocytes and platelets. Here, we show that low expression of Gfi1b in blast cells is associated with an inferior prognosis of MDS and AML patients. Using different models of human MDS or AML, we demonstrate that AML development was accelerated with heterozygous loss of Gfi1b, and latency was further decreased when Gfi1b was conditionally deleted. Loss of Gfi1b significantly increased the number of leukemic stem cells with upregulation of genes involved in leukemia development. On a molecular level, we found that loss of Gfi1b led to epigenetic changes, increased levels of reactive oxygen species, as well as alteration in the p38/Akt/FoXO pathways. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS and AML development.

PMID:
29326122
PMCID:
PMC5865438
DOI:
10.3324/haematol.2017.167288
[Indexed for MEDLINE]
Free PMC Article

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