Regulation by bcl-2, c-myc, and p53 of susceptibility to induction of apoptosis by heat shock and cancer chemotherapy compounds in differentiation-competent and -defective myeloid leukemic cells.
Myeloid leukemias that differ in their competence for induction of differentiation were analyzed for expression of bcl-2 and c-myc and for their sensitivity to induction of apoptosis by heat shock and cancer chemotherapy compounds. The M1 leukemia expressed a high level of bcl-2 and showed a much lower susceptibility to induction of apoptosis by heat shock, Adriamycin, 1-beta-D-arabinofuranosylcytosine, methotrexate, and cycloheximide, compared to five other leukemias which expressed a low level of bcl-2. There was no association between susceptibility to induction of apoptosis and competence for induction of differentiation. The difference in susceptibility to methotrexate, which is not regulated by the multidrug resistance (MDR) genes, and treatment with verapamil, which blocks MDR activity, have indicated that the higher resistance of the M1 leukemia to these agents was not due to MDR activity. The results indicate that the level of regulated bcl-2 expression in these myeloid leukemias was associated with cell susceptibility to induction of apoptosis by different apoptosis-inducing agents. Screening for expression of bcl-2 may thus be useful to characterize leukemias regarding susceptibility to induction of apoptosis by different agents. The level of regulated c-myc expressed in these leukemias was not associated with susceptibility to induction of apoptosis. Transfection with a deregulated mutant p53 into the M1 leukemia did not change susceptibility to apoptosis induction, but transfection with deregulated c-myc increased susceptibility to apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Lotem
J
J
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Sachs
L
L
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D016259:Genes, myc / Q000235:genetics*; D006358:Hot Temperature; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D003513:Cycloheximide