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An isoform-specific C/EBPβ inhibitor targets acute myeloid leukemia cells

Leukemia volume 30, pages 1612–1615 (2016)Cite this article

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Targeting of oncogenic transcription factors with small-molecule inhibitors is an important goal as it offers great potential for the development of novel therapeutic strategies. c-Myb, a transcription factor highly expressed in the hematopoietic system, is now emerging as a potential target for the development of small-molecule inhibitors for the treatment of leukemia and several other cancers.1, 2 Interest in c-Myb as a drug target has been fostered by the identification of gene rearrangements suggesting a causal role of c-Myb in the development of acute lymphoblastic leukemia3, 4, 5 and by the demonstration that acute myeloid leukemia (AML) cells are often ‘addicted’ to high levels of c-Myb expression, making them more vulnerable to c-Myb inhibition than normal hematopoietic progenitor cells.6, 7

We have previously shown that the sesquiterpene lactone mexicanin-I also inhibits Myb activity in our reporter cell line.8 Because mexicanin-I and helenalin acetate are structurally closely related (mexicanin-I is a stereoisomer of nonesterified helenalin), we investigated if mexicanin-I also inhibits C/EBPβ activity. Using the activation of the C/EBP target gene MRP126 to measure C/EBPβ activity, we found that mexicanin-I also inhibits the activity of C/EBPβ; however, mexicanin-I was less potent than helenalin (Supplementary Figure S1). This indicated that the inhibitory activity of these compounds is highly dependent on their specific spatial structures.

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Acknowledgements

We thank B Berkenfeld, P Pieloch and B Lindtner for technical assistance and C Scheidereit for plasmids. This work was supported by the Deutsche Krebshilfe, the Deutsche Jose Carreras Leukämie-Stiftung e.V. and the Adenoid Cystic Carcinoma Research Foundation (ACCRF).

Author contributions

AJ, SU and K-HK designed and performed the experiments, analyzed the data and wrote the manuscript. AC, SS and CS designed and performed the experiments and analyzed the data. TJS and CM-T designed the experiments, analyzed the data and wrote the manuscript. PS and WEB provided patient material and wrote the manuscript.

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Authors and Affiliations

  1. Institute for Biochemistry, Westfälische Wilhelms-Universität, Münster, Germany

    A Jakobs, S Uttarkar, S Steinmann, A Coulibaly & K-H Klempnauer

  2. Institute for Pharmaceutical Biology and Phytochemistry, Westfälische Wilhelms-Universität, Münster, Germany

    C Schomburg & T J Schmidt

  3. Department of Blood Group Serology and Transfusion Medicine, Medical University Graz, Graz, Austria

    P Schlenke

  4. Department of Medicine A, Hematology and Oncology, Westfälische Wilhelms-Universität, Münster, Germany

    W E Berdel

  5. Department of Medicine, Hematology and Oncology, University of Halle, Halle, Germany

    C Müller-Tidow

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  1. A Jakobs
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Correspondence to K-H Klempnauer.

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Jakobs, A., Uttarkar, S., Schomburg, C. et al. An isoform-specific C/EBPβ inhibitor targets acute myeloid leukemia cells. Leukemia 30, 1612–1615 (2016). https://doi.org/10.1038/leu.2016.16

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