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

Leukemia. 1995 Sep;9(9):1467-72.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / genetics
  • Cell Cycle
  • Granulocyte-Macrophage Colony-Stimulating Factor* / administration & dosage
  • Granulocyte-Macrophage Colony-Stimulating Factor* / pharmacology
  • Humans
  • Leukemia, Promyelocytic, Acute / metabolism*
  • Leukemia, Promyelocytic, Acute / pathology*
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Oncogene Proteins, Fusion / metabolism
  • Oncogene Proteins, Fusion / physiology*
  • Time Factors
  • Tumor Cells, Cultured


  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
  • Granulocyte-Macrophage Colony-Stimulating Factor