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DNA released by leukemic cells contributes to the disruption of the bone marrow microenvironment

Oncogene volume 32, pages 5201–5209 (2013)Cite this article

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Abstract

Reciprocal interactions between a tumor and its microenvironment control expansion of tumor cells. Here we show a specific type of interaction in which blasts of experimental leukemia destroy the bone marrow (BM) structures and kill stromal cells. The in vitro experiments showed that the cytotoxic agent released by leukemic cells is the fragmented DNA derived from their genome and occurring in nucleosome-like complexes. This DNA entered nuclei of BM or other cells and induced H2A.X phosphorylation at serine 139, similar to double-strand break-inducing agents. There was a correlation between large amounts of acquired DNA and death of recipient cells. Moreover, the DNA integrated into chromosomal DNA of recipient cells. Primary human acute myeloid leukemia cells also released fragmented DNA that penetrated the nuclei of other cells both in vitro and in vivo. We suggest that DNA fragments released from leukemic and also perhaps other types of tumor cells can activate DNA repair mechanisms or death in recipient cells of a tumor microenvironment, depending on the amount of the acquired DNA. This can impair DNA stability and viability of tumor stromal cells, undermine homeostatic capacity of tumor microenvironment and facilitate tumor progression.

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Acknowledgements

We thank Professor Milos Grim and Drs Vladimir Pecenka, Vladimir Cermak and Jan Kosla for critical comments on manuscript. We are indebted to Drs Petr Novak, Vladimir Havlicek and Petr Pompach for identification of proteins by mass spectrometry, to Drs A Ekefjärd and D Enetoft from Ludesi for providing Viper software, and to Dr David W Hardekopf for his help in manuscript preparation. This work was supported by Grants AV0Z50520514 and KAN200520801 from the Academy of Sciences of the Czech Republic and LC06061 from the Ministry of Education, Youth and Sports and 204/06/1728 and 301/09/1727 from the Grant Agency of the Czech Republic to MD and from the Internal Grant Agency of the Ministry of Health of the Czech Republic, Grant no. NR 9651-4 to SP. We are also indebted to Tomáš Hlavnička, Roman Minárik, Miroslav Navrátil, Leoš Navrátil, Vladimír Pečenka, Karel Rybáček, Miroslav Sobotka, Josef Soukal and Petr Streitberg for financial support.

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Authors and Affiliations

  1. Institute of Molecular Genetics, AS CR, Prague, Czech Republic

    M Dvořáková, V Karafiát, P Pajer & M Dvořák

  2. Institute of Anatomy, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic

    E Kluzáková

  3. Institute of Animal Physiology and Genetics, AS CR, Libechov, Czech Republic

    K Jarkovská

  4. Chambon Laboratory of Molecular Diagnostics, Prague, Czech Republic

    S Peková & L Krutílková

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  1. M Dvořáková
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Correspondence to M Dvořák.

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Dvořáková, M., Karafiát, V., Pajer, P. et al. DNA released by leukemic cells contributes to the disruption of the bone marrow microenvironment. Oncogene 32, 5201–5209 (2013). https://doi.org/10.1038/onc.2012.553

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