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Investigation of C/EBPα function in human (versus murine) myelopoiesis provides novel insight into the impact of CEBPA mutations in acute myelogenous leukemia (AML)

Leukemia volume 23, pages 978–983 (2009)Cite this article

The CEBPA gene, encoding the CCAAT/enhancer-binding protein-α (C/EBPα) transcription factor, is mutated in approximately 10% of acute myelogenous leukemia (AML).1 The discovery of these mutations confirmed a long-standing hypothesis that the disruption of genes regulating differentiation is a critical step in leukemogenesis.2 The importance of C/EBPα in myeloid differentiation was first recognized due to its pivotal role in the regulation of myeloid-specific genes; however, the most compelling evidence came from studies on knockout mice, its ablation resulting in a differentiation block at the myeloblast stage.3 More recent data have pinpointed the block at the transition from a common myeloid progenitor (CMP) to a granulocyte-macrophage progenitor (GMP), but this can be overcome by stimulation with GM colony-stimulating factor or interleukin-3. These cytokines presumably activate an alternative pathway of ‘emergency’ granulopoiesis, involving C/EBPβ.3 Unfortunately, these cytokines are unable to reverse the differentiation block observed in human AML,4 suggesting distinct control mechanisms in human myelopoiesis and/or a more complex mechanism by which differentiation is blocked in AML. In favor of the former hypothesis, we have shown earlier that the ectopic expression of a C/EBPα mutant found in AML patients has different effects in mouse versus human hematopoietic cells.5 In the study presented here, we have investigated possible mechanisms behind this difference.

The majority of CEBPA mutations results in the translation of an N-terminal truncated C/EBPα protein, termed p30, that lacks two of three transactivation elements that are important for recruiting the transcription apparatus but also binding and inhibiting the E2F complex, an important regulator of cell-cycle progression.1 Thus, it would be predicted that p30 has lost important functional attributes necessary for driving myelocytic differentiation, including regulation of lineage-specific genes and the induction of growth arrest that occurs at the metamyelocytic stage of differentiation. Furthermore, the reported dominant-negative activity of p30 on the transcriptional function of wt C/EBPα, presumably through the formation of heterodimerization, would also limit the activity of the non-mutated CEBPA allele.6 Somewhat surprisingly, we have shown earlier that ectopic p30 expression in murine myeloid progenitors induces myeloid differentiation, albeit with altered proliferation kinetics.5 A recent study has confirmed these results; mice engineered to heterozygously express p30 from the Cebpa allele display normal granulopoiesis.7 Notably, however, mice homozygous for this altered allele develop AML with a penetrance of 100%. One interpretation is that the p30 form is indeed still able to drive the transition to the GM progenitor stage and that its inability to efficiently regulate cell cycle control through E2F leads to a myeloproliferation, which progresses into AML.

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Acknowledgements

We thank Alan Friedman (Baltimore, MD) for providing critical constructs for these studies and for discussion. We are also indebted to Uwe Herwig, MD, and his team at the Albertinen-Krankenhaus, Hamburg, for supplying umbilical cord blood. Experiments using primary human cells were approved by the Ethics Committee of the Ärtztekammer Hamburg. We acknowledge with special thanks the contribution of Ulla Bergholz, Arne Düsedau and Marion Zeigler in assisting with experiments. This study was supported by grants from the Deutsche José Carreras Leukämie Stiftung (CS), the Deutsche Krebshilfe (JC and CS) and the Werner Otto Stiftung (GI). The Heinrich-Pette-Institut is supported by the Freie und Hansestadt Hamburg and the Bundesministerium für Gesundheit und soziale Sicherung.

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  1. B Niebuhr and G B Iwanski: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Pathology, Heinrich-Pette-Institut für experimentelle Virologie und Immunologie, Hamburg, Germany

    B Niebuhr, G B Iwanski, M Schwieger, S Roscher, C Stocking & J Cammenga

  2. Department of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund, Sweden

    J Cammenga

  3. Department of Hematology, Lund University Hospital, Lund, Sweden. E-mail: stocking@hpi.uni-hamburg.de,

    J Cammenga

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  1. B Niebuhr
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Niebuhr, B., Iwanski, G., Schwieger, M. et al. Investigation of C/EBPα function in human (versus murine) myelopoiesis provides novel insight into the impact of CEBPA mutations in acute myelogenous leukemia (AML). Leukemia 23, 978–983 (2009). https://doi.org/10.1038/leu.2008.332

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