MLL rearrangements are induced by low doses of etoposide in human fetal hematopoietic stem cells

摘要: During fetal development, the liver serves as primary hematopoietic organ in which stem cells (HSC) comprise a large proportion of hepatic cell populations. Because HSC are capable initiating long-term hematopoiesis, injury to these during pregnancy may play role development disorders manifested after birth. Of interest is genetic etiology infant acute leukemias, characterized by chromosomal rearrangements 11q23 region involving mixed lineage leukemia (MLL) gene. These gene fusions also occur leukemias adults following chemotherapy with etoposide and other inhibitors DNA topoisomerase II. We used model compound determine sensitivity human damage whether we could induce MLL cultured HSC. Exposure resulted dose-dependent loss viability, effects observed at low nanomolar concentrations. strand breaks were on exposure 140 nM etoposide, higher concentrations stimulated an increase early lymphoid populations elicited G2/M cycle arrest. Immunophenotyping translocations revealed significant positive flow cytometry events consistent recombination. confirmed using fluorescent situ hybridization. In vitro inhibition II was >or=25 microM but not evident lower associated damage. Our data indicate that doses can cause Ultimately, such have ramifications regards transplacental exposures environmental chemicals linked leukemias.