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.
The development of red blood cells from hematopoietic progenitors requires the interplay of speci®c extracellular factors and transcriptional regulators. Here we have identi®ed an erythroid progenitor that is critically dependent on bFGF and requires expression of AMV v-Myb for sustained proliferation in vitro, indicating that bFGF and Myb proteins cooperate in these cells. In the presence of bFGF such v-Myb cells are completely blocked in their ability to di erentiate and exhibit an exceptionally high proliferative potential and long lifespan in vitro. Interestingly, in the absence of bFGF cells e ectively di erentiate into mature erythrocytes, irrespective of constitutive and elevated levels of v-Myb. We also demonstrate that these cells express high levels of FGF receptor type 1 (FGFR1) and that phospholipase Cg (PLCg) is one of the important molecules in FGF receptor signaling. Our studies suggest that bFGF, in cooperation with Myb proteins, represents an important factor for determining erythroid lineage choice. These ®ndings unravel a so far unidenti®ed link between extracellular signaling and Myb in hematopoietic cells.
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