Control of sensitivity to induction of apoptosis in myeloid leukemic cells by differentiation and bcl-2 dependent and independent pathways.
Induction of differentiation in M1 myeloid leukemic cells by the hematopoietic cytokines interleukin 6 and granulocyte-colony stimulating factor, or by the glucocorticoid dexamethasone, was associated with down-regulation of the apoptosis inhibiting gene bcl-2. The cytokine treated leukemic cells showed an increased sensitivity to induction of apoptotic cell death by the cancer chemotherapy compounds Adriamycin and cytosine arabinoside and by heat shock and cycloheximide. Dibutyryl cyclic AMP neither induced differentiation nor down-regulated bcl-2 expression, but it sensitized the cells to induction of apoptosis by some of these agents. Although dexamethasone induced differentiation and down-regulated bcl-2 expression, it did not sensitize the cells to induction of apoptosis and inhibited the apoptosis sensitizing effect of the cytokines and dibutyryl cyclic AMP. Dexamethasone did not inhibit induction of apoptosis by wild-type p53 or viability factor withdrawal. The apoptosis sensitizing effect of the cytokines and dibutyryl cyclic AMP was reversible upon their withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)
Lotem
J
J
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Sachs
L
L
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016179:Granulocyte Colony-Stimulating Factor; D003994:Bucladesine; D003907:Dexamethasone