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C/EBPδ expression in a BCR-ABL-positive cell line induces growth arrest and myeloid differentiation

Oncogene volume 24, pages 1589–1597 (2005)Cite this article

Abstract

CCAAT/enhancer-binding proteins (C/EBPs) are a family of highly conserved transcription factors that have important roles in normal myelopoiesis as well as associated with myeloid disorders. The chronic myelogenous leukemia (CML) cell lines, KCL22 and K562, express exceptionally low levels of endogenous C/EBPs and provide a good model to test the effects of C/EBPs on myeloid differentiation. To explore the possibility that C/EBPδ can promote differentiation in BCR-ABL-positive cells, we generated stable KCL22 and K562 clones that expressed an inducible C/EBPδ gene. C/EBPδ expression resulted in G0/G1 proliferative arrest and a moderate increase in apoptosis of the KCL22 and the K562 cells. Within 4 days of inducing expression of C/EBPδ, myeloid differentiation of the CML blast cells occurred as shown by morphologic changes and induction of secondary granule-specific genes. We also showed that during granulocytic differentiation of KCL22 cells, the C/EBPδ protein was detected in immunocomplexes with both Rb and E2F1. Furthermore, expression of C/EBPδ was associated with downregulation of c-Myc and cyclin E and upregulation of the cyclin-dependent kinase inhibitor p27Kip1 in both the KCL22 and K562 cell lines. These results show that expression of C/EBPδ in BCR-ABL-positive leukemic cells in blast crisis is sufficient for neutrophil differentiation and point to the therapeutic potential of ectopic induction of C/EBPδ in the acute phase of CML.

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Acknowledgements

This work was supported in part by National Institutes of Health grants as well as the Ronald Havner, Parker Hughes, and the Cindy and Alan Horn funds. HPK is a member of the Jonsson Comprehensive Cancer Center and the Molecular Biology Institute (UCLA) and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine.

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  1. Sigal Gery and Sakae Tanosaki: These authors contributed equally to the manuscript.

Authors and Affiliations

  1. Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, 90048, USA

    Sigal Gery, Sakae Tanosaki, Ahrin Koppel & H Phillip Koeffler

  2. Department of Hematology, University Hospital, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany

    Wolf-K Hofmann

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  1. Sigal Gery
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  2. Sakae Tanosaki
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Correspondence to Sigal Gery.

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Gery, S., Tanosaki, S., Hofmann, WK. et al. C/EBPδ expression in a BCR-ABL-positive cell line induces growth arrest and myeloid differentiation. Oncogene 24, 1589–1597 (2005). https://doi.org/10.1038/sj.onc.1208393

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