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Acute Leukemias

Overexpression of wild-type or mutants forms of CEBPA alter normal human hematopoiesis

Leukemia volume 26, pages 1537–1546 (2012)Cite this article

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Abstract

CCAAT/enhancer-binding protein-α (C/EBPα/CEBPA) is mutated in approximately 8% of acute myeloid leukemia (AML) in both familial and sporadic AML and, with FLT3 and NPM1, has received most attention as a predictive marker of outcome in patients with normal karyotype disease. Mutations clustering to either the N- or C-terminal (N- and C-ter) portions of the protein have different consequences on the protein function. In familial cases, the N-ter form is inherited with patients exhibiting long latency period before the onset of overt disease, typically with the acquisition of a C-ter mutation. Despite the essential insights murine models provide the functional consequences of wild-type C/EBPα in human hematopoiesis and how different mutations are involved in AML development have received less attention. Our data underline the critical role of C/EBPα in human hematopoiesis and demonstrate that C/EBPα mutations (alone or in combination) are insufficient to convert normal human hematopoietic stem/progenitor cells into leukemic-initiating cells, although individually each altered normal hematopoiesis. It provides the first insight into the effects of N- and C-ter mutations acting alone and to the combined effects of N/C double mutants. Our results mimicked closely what happens in CEBPA mutated patients.

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Acknowledgements

We thank the members of FACS service and animal facilities for their help. We are grateful to Dr Oscar Escribano from Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain for his technical advice in performing the western blot analysis. This project was supported by Cancer Research UK and by European grant (contract no: 037632) to DB. OQ-B was supported by CRUK, LRI fellowship.

Author Contributions

OQ-B designed and performed research, analyzed and interpreted data, performed statistical analysis and wrote paper. SL-LS, EG, YR and JV performed part of the research experiments, TAL provided vital materials and JF interpreted data and wrote paper, DB designed research and analyzed and interpreted data and wrote paper.

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Authors and Affiliations

  1. Haematopoietic Stem Cell Laboratory, Cancer Research UK, London, UK

    O Quintana-Bustamante, E Griessinger, Y Reyal, J Vargaftig & D Bonnet

  2. Department of Haematological Medicine, Leukaemia and Stem Cell Biology Laboratory, King's College of London, London, UK

    S Lan-Lan Smith

  3. Department of Medical Oncology, St Bartholomew's Hospital, Queen Mary University of London, London, UK

    T A Lister

  4. Centre of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK

    J Fitzgibbon

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Quintana-Bustamante, O., Smith, SL., Griessinger, E. et al. Overexpression of wild-type or mutants forms of CEBPA alter normal human hematopoiesis. Leukemia 26, 1537–1546 (2012). https://doi.org/10.1038/leu.2012.38

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