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Acute myeloid leukemia

TP53 deficiency permits chromosome abnormalities and karyotype heterogeneity in acute myeloid leukemia

Leukemia volume 33, pages 2619–2627 (2019)Cite this article

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Abstract

Abnormal karyotypes are common in cancer cells and frequently observed in acute myeloid leukemia (AML), in which complex karyotype aberrations are associated with poor prognosis. How exactly abnormal karyotypes arise and are propagated in AML is unclear. TP53 mutations and deletions are frequent in complex karyotype AML, suggesting a role of TP53 alterations in the development of chromosome abnormalities. Here, we generated isogenic TP53-knockout versions of the euploid AML cell line EEB to investigate the impact of TP53 on karyotype stability. We show that chromosome abnormalities spontaneously arise in TP53-deficient cells. Numerical aneuploidy could, to some extent, be propagated in a TP53-proficient setting, indicating that it does not necessarily trigger TP53 activation. In contrast, tolerance to structural chromosome aberrations was almost entirely restricted to TP53-knockout clones, all of which were able to continue proliferation in the presence of damaged DNA. Mechanistically, as a source of chromosome aberrations, limited numerical but not structural chromosomal instability was tolerated by TP53-wildtype cells. In contrast, structural instability was found only in TP53-knockout cells. Together, in myeloid cells TP53 loss allows for the development of complex karyotype aberrations and karyotype heterogeneity by perpetuation of chromosome segregation errors.

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Acknowledgements

We thank Brigitte Schoell for excellent technical assistance.

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Authors and Affiliations

  1. Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    Anna Cazzola, Christin Schlegel, Ilka Jansen, Tilmann Bochtler & Alwin Krämer

  2. Department of Thoracic Oncology, Thoraxklinik Heidelberg, University of Heidelberg, Heidelberg, Germany

    Tilmann Bochtler

  3. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    Tilmann Bochtler & Alwin Krämer

  4. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

    Anna Jauch

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Contributions

A.C. and A.K. designed the experiments and analyzed the data; A.C., C.S., I.J., T.B., and A.J. performed the experiments; and A.C. and A.K. wrote the manuscript.

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Correspondence to Alwin Krämer.

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This work was supported by grants of the Deutsche Forschungs gemeinschaft (DFG, KR 1981/4-1), the Wilhelm Sander-Stiftung, and a University of Heidelberg research trust to AK. The authors declare no competing financial interests.

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Cazzola, A., Schlegel, C., Jansen, I. et al. TP53 deficiency permits chromosome abnormalities and karyotype heterogeneity in acute myeloid leukemia. Leukemia 33, 2619–2627 (2019). https://doi.org/10.1038/s41375-019-0550-5

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