BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death.
Apoptosis is the major form of cell death associated with the action of chemotherapeutic agents on tumor cells, and therefore the expression of genes that interfere with apoptosis can have important consequences for the efficacy of therapeutic approaches. Here we show that K562, a chronic myelogenous leukemia (CML) cell line expressing the BCR-ABL fusion protein, are resistant to the induction of apoptosis by a number of agents and conditions. Antisense oligodeoxynucleotides corresponding to the translation start of bcr downregulate bcr-abl protein in these cells and render them susceptible to induction of apoptosis by chemotherapeutic agents or serum deprivation. Expression of a temperature sensitive v-Abl protein reverses the effects of the antisense oligonucleotides, such that the cells remain resistant to apoptosis at the permissive temperature. These data indicate that bcr-abl acts as an anti-apoptosis gene in CML cells and suggests that the effect is dependent on the abl kinase activity in this chimeric protein. Inhibition of bcr-abl to render CML cells susceptible to apoptosis can be combined with therapeutic drugs and/or treatment capable of inducing apoptosis to provide an effective strategy for elimination of these cells.
McGahon
A
A
Department of Biology, St Patrick's College, Kildare, Ireland.
Bissonnette
R
R
Schmitt
M
M
Cotter
K M
KM
Green
D R
DR
Cotter
T G
TG
D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl