Differentiation-induced ML-1 cells as targets for transformation by a chemical carcinogen.
The capacity for continuous proliferation (immortalization) of ML-1 human myeloblastic leukemia cells derives from their sensitivity to growth factors and their insensitivity to differentiation factors (DF) at the limiting concentrations at which these are present in the culture medium. Upon increasing the concentration of DF, or after treatment with DNA-specific anticancer agents, the cells exit the proliferation program and differentiate to monocyte/macrophage-like cells (Y. Honma, C. Honma, and A. Bloch, Cancer Res., 46: 6311-6315, 1986). The study reported here shows that when ML-1 cells, induced to differentiate with DF contained in mitogen-stimulated human leukocyte-conditioned medium (CM) are treated with the carcinogen N-nitroso-N-methylurea, their differentiation program is interrupted and proliferation is resumed at a stably increased rate of growth (doubling time, 25.1 versus 31.3 h). This "step-up" transformation is brought about by only a narrow concentration range of carcinogen, acting at a restricted time interval following differentiation induction. The step-up transformed cells are more sensitive to growth factor signals and less sensitive to DF signals than are untreated ML-1 cells. When retreated with a higher concentration of DF and the same concentration of N-nitroso-N-methylurea, the transformed cells undergo a further decrease in doubling time to 21 h. Differentiation-uninduced ML-1 cells do not respond to treatment with N-nitroso-N-methylurea, indicating that differentiation-induced cells, at an early stage of the maturation process, may be the targets for the carcinogen-mediated transformation.
Guan
X P
XP
Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York 14263.
Bloch
A
A
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004247:DNA / Q000187:drug effects; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008770:Methylnitrosourea / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude
D008770:Methylnitrosourea; D004247:DNA