The acute promyelocytic leukemia-specific PML/RAR alpha fusion protein reduces the frequency of commitment to apoptosis upon growth factor deprivation of GM-CSF-dependent myeloid cells.
PML/RAR alpha is the putative transforming sequence of acute promyelocytic leukemias. We investigated the effects of PML/RAR alpha on cell survival by expressing the fusion protein in the growth factor-dependent TF-1 cell line and analyzing the kinetics of cell death after GM-CSF deprivation. Results showed that PML/RAR alpha expression markedly delayed apoptotic cell death (3 weeks vs 1 week) without inducing growth factor independence. Growth factor deprivation caused rapid and massive apoptosis of control TF-1 cells (>95% apoptotic cells after 4-5 days). Factor-deprived control cells were synchronously and irreversibly committed to apoptosis as shown by their inability to re-enter the cell cycle after GM-CSF re-addition. The percentage of apoptotic cells in the PML/RAR alpha expressing cells was low (approximately 30-35%) and constant over the 4 weeks of factor deprivation. GM-CSF re-addition produced rapid increase in cell number at all time points during the 4 weeks of factor deprivation, suggesting that commitment to apoptosis was asynchronous and delayed in PML/RAR alpha-expressing TF-1 cells. We conclude that PML/RAR alpha interferes with the genetic pathways which regulate survival by reducing the frequency of commitment to apoptosis. This biological effect of PML/RAR alpha may contribute to its leukemogenetic potential.
Rogaia
D
D
Istituto di Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, Perugia University, Italy.
Grignani
F
F
Grignani
F
F
Nicoletti
I
I
Pelicci
P G
PG
D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor