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

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.