Page 70 - Haematologica-April 2018

Correspondence:
cyrus.khandanpour@uk-essen.de
Received: June 29, 2017. Accepted: January 5, 2018. Pre-published: January 11, 2018.
doi:10.3324/haematol.2017.167288
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Acute Myeloid Leukemia
Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome
Aniththa Thivakaran,1 Lacramioara Botezatu,1 Judith M. Hönes,1,2
Judith Schütte,1 Lothar Vassen,1 Yahya S. Al-Matary,1 Pradeep Patnana,1 Amos Zeller,1 Michael Heuser,3 Felicitas Thol,3 Razif Gabdoulline,3 Nadine Olberding,1 Daria Frank,1 Marina Suslo,1 Renata Köster,1
Klaus Lennartz,4 Andre Görgens,5,6 Bernd Giebel,5 Bertram Opalka,1 Ulrich Dührsen1 and Cyrus Khandanpour1,7
1Department of Haematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 2Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 3Department of Haematology, Haemostaseology, Oncology, and Stem Cell Transplantation, Medical University of Hannover, Germany; 4Institute for Cell Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 5Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 6Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden and 7Department 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 myelodys- plastic syndrome (MDS) or acute myeloid leukemia (AML). Growth fac- tor independence 1b (Gfi1b) is a repressing transcription factor regulating quiescence of hematopoietic stem cells and differentiation of erythro- cytes 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 func- tions as an oncosuppressor in MDS and AML development.
Introduction
Myelodysplastic syndrome (MDS) is characterized by disturbed function of the myeloid compartment of the bone marrow (BM),1 leading in some cases to acute myeloid leukemia (AML).2 AML is characterized by an accumulation of immature myeloid blasts in the BM.2 Hematopoietic development, among other functions, is regulated by transcription factors (TFs).3 Functional dysregulation of several TFs4,5 can induce malignant transformation. The hematopoieticTF Growth factor independence 1b (Gfi1b) regulates dormancy and proliferation6 of hematopoietic stem cells (HSCs), the development of erythroid and megakaryocytic cells,7-10 as well as B and T cells.11- 13 Constitutive deletion of Gfi1b in mice is embryonically lethal at day E15 due to bleeding and anemia.9 Conditional loss of Gfi1b leads to a significant expansion of functional HSCs in the BM and peripheral blood.6 In human primary hematopoietic progenitors, forced expression of GFI1B results in expansion of immature erythrob- lasts and repression of myeloid differentiation.14 Gfi1b exerts its function by recruiting histone modifying enzymes, such as CoREST, G9a, LSD1 or HDACs, to induce deacetylation of H3K9, demethylation of H3K4 and/or methylation of H3K9.15-18 We report that a reduced level or absence of GFI1B negatively influences the prognosis of MDS/AML patients. Moreover, we present evidence that loss/reduced expression of Gfi1b promotes AML development in different murine models of human AML.
Haematologica 2018 Volume 103(4):614-625
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haematologica | 2018; 103(4)
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