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Lymphoma

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

Leukemia volume 26, pages 2508–2516 (2012)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10–15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients.

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Acknowledgements

This work was supported by Klinische Malignom und Zytokinforschung Salzburg-Innsbruck GmbH (RG), the Jubiläumsfond der Österreichischen Nationalbank (Grant 12170 to RG), Spezialforschungsprogramm P021 (RG), Fonds zur Förderung der wissenschaftlichen Forschung P-18478-B12 (LK), L488-B13 (AE), P19481-B12 (AE), the Genome Austria Research project ‘Inflammobiota’ (LK) and the Novus Sanguis Consortium, LeJeune Foundation (LK). We are grateful to Richard Moriggl for critical discussion of the manuscript.

AUTHOR CONTRIBUTIONS

OM and NW designed the research. NW, ES, TM, FH and TK performed the experimental work; M Schl and LK performed H&E stains of FFPE tissues; MS provided patient material; M Sche produced mRNA arrays; UD, JPH, AE performed murine experiments; OM and NW wrote the paper; OM, LK and RG did the final approval and correction of the manuscript. OM, LK and RG contributed to project development and obtained funding.

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  1. O Merkel and N Wacht: These authors contributed equally to this work.

Authors and Affiliations

  1. 3rd Medical Department with Hematology, Laboratory for Immunological and Molecular Cancer Research, Medical Oncology, Hemostaseology, Rheumatology and Infectiology of the Paracelsus Medical University Hospital, Salzburg, Austria

    O Merkel, N Wacht, E Sifft, T Melchardt, F Hamacher, T Kocher, U Denk, J P Hofbauer, A Egle & R Greil

  2. Institute for Genomics and Bioinformatics, Graz University of Technology, Graz, Austria

    M Scheideler

  3. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    M Schlederer & L Kenner

  4. Department of Internal Medicine V, Laboratory for Molecular Genetics, Innsbruck Medical University, Innsbruck, Austria

    M Steurer

  5. Institute for Clinical Pathology, Medical University Vienna, Vienna, Austria

    L Kenner

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  1. O Merkel
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Merkel, O., Wacht, N., Sifft, E. et al. Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia. Leukemia 26, 2508–2516 (2012). https://doi.org/10.1038/leu.2012.147

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