ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block.
Using a temperature-sensitive mutant of the p210 BCR-ABL gene, transfected into a growth factor-dependent cell line (BaF3), we show that transient BCR-ABL kinase expression increases single cell and clonogenic resistance to apoptosis arising from genotoxic damage induced by ionizing radiation and VP-16/etoposide. This effect is achieved in the absence of any detectable changes in the levels of BCL-2, BAX or BCL-x proteins and is independent of proliferative, MAP kinase-dependent effects of BCR-ABL kinase. In contrast to parental cells that transiently arrest in G2 and then apoptose, p210 BaF3 cells show a pronounced and sustained G2 arrest following radiation coupled with enhanced phosphorylation of cdc2. A cell cycle block in early M phase induced by the mitotic spindle poison, nocodazole, does not provide protection from apoptosis. Reversal of G2 arrest by caffeine abolishes the protective effect of BCR-ABL kinase. These data provide further insight into the transforming properties of BCR-ABL and are relevant to the clinical intransigence of Ph-positive leukaemias.
Nishii
K
K
Leukaemia Research Fund Centre, Institute of Cancer Research, London, UK.
Kabarowski
J H
JH
Gibbons
D L
DL
Griffiths
S D
SD
Titley
I
I
Wiedemann
L M
LM
Greaves
M F
MF
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002110:Caffeine / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects / Q000528:radiation effects; D004790:Enzyme Induction / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D007377:Interleukin-3 / Q000494:pharmacology*; D008938:Mitosis / Q000528:radiation effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011836:Radiation Tolerance; D013696:Temperature; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000972:Antineoplastic Agents, Phytogenic; D007377:Interleukin-3; D010726:Phosphodiesterase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D002110:Caffeine; D005047:Etoposide; D011494:Protein Kinases; D016044:Fusion Proteins, bcr-abl