LONG-TERM PROTECTION OF HEMATOPOIESIS AGAINST THE CYTOTOXIC EFFECTS OF MULTIPLE DOSES OF NITROSOUREA BY RETROVIRUS-MEDIATED EXPRESSION OF HUMAN O-6-ALKYLGUANINE-DNA-ALKYLTRANSFERASE

A human O-6-alkylguanine-DNA-alkyltransferase (ATase) cDNA-containing retrovirus was used to infect murine longterm primary bone marrow cult ures. High levels of ATase expression were obtained. and colony-formin g cells of the granulocyte-macrophage lineage from the cultures transd uced with the human ATase retrovirus were three times more resistant t o the alkylating agent, N-methyl-N-nitrosourea (MNU). than control cul tures. Furthermore, expression of the human ATase protected long-term hematopoiesis, measured as the output of progenitor cells to the nonad herent fraction of the culture, against the cytotoxic effects of repea ted exposures to MNU. These results clearly show that a human ATase cD NA-containing retrovirus can be used to infect long-term primary bone marrow cultures and that this attenuates their sensitivity to nitrosou reas. (C) 1996 by The American Society of Hematology.