bcr/abl expression in 32D cl3(G) cells inhibits apoptosis induced by protein tyrosine kinase inhibitors.
Eight protein tyrosine kinase inhibitors with in vitro epidermal growth factor receptor kinase 50% inhibitory concentration values ranging from 0.043 to 22 microM were studied for their ability to inhibit the growth of the murine interleukin-3 (IL-3) dependent myeloid 32D cl3(G) cell line and, a subclone (LG7) transformed to IL-3 independent growth by retroviral transduction and expression of the chronic myelogenous leukemia-associated protein tyrosine kinase p210bcr/abl. Cell proliferation 50% inhibitory concentration values ranged from 4 to 250 microM, and one compound was not inhibitory at 500 microM. The dose-cell proliferation curves were remarkably similar for parental 32D cl3(G) cells + IL-3 and LG7 +/- IL-3, and reversion of LG7 cells to IL-3 dependence was not observed, suggesting that none of the compounds tested could selectively inhibit p210bcr/abl. However, 6 compounds induced the appearance of a 200-base pair nucleosomal DNA ladder characteristic of apoptosis at 24 h in parental 32D cl3(G) cells + IL-3, which mimicked the effects of IL-3 withdrawal alone, but not in similarly growth arrested LG7 cells that eventually developed a necrotic pattern of DNA fragmentation. These studies suggest that the expression of p210bcr/abl can suppress apoptotic signal transduction and that this may contribute to the development of the myeloid hyperplasia that occurs in chronic phase chronic myelogenous leukemia.
Laneuville
P
P
Department of Medicine, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada.
Timm
M
M
Hudson
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AT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018014:Gene Transfer Techniques; D006413:Hematopoietic System / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000502:physiology
D007377:Interleukin-3; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl