The acute promyelocytic leukemia-specific PML/RARa fusion protein reduces sensitivity to apoptosis upon tnfot stimulation

U. Testa, F. Grianoni, P. Samoggia, R. Masciulli, C. Zanetti, R. Riccioni, C. Gambacorti Passerini, M. Grell, P. G. Pelicci, C. Peschle

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Abstract

Acute promyelocytic leukemia (API) is characterized by the accumulation of blasts blocked at the promyelocytic stage of differentiation. Major features of APL cells include: (I) block of differentiation; (ii) high sensitivity to the differentiative action of retinoic acid (RA); (iii) increased cell survival. The mechanisms through which the APL-specific fusion protein PML/RARa blocks differentiation and allows cell maturation upon RA treatment have been elucidated. However, the mechanisms responsible for the improvement of cell survival mediated by PML/RARa are largely unknown. We have observed a protective effect of PML/RARa expression on TNFa mediated apoptosis using U937 cells as target against apoptosis mediated by TNFa; this protective effect was also observed when cytotoxicity was triggered by agonistic anti-TNF receptor I and II antibodies. The protective action of PML/RARa was specific for TNFa mediated cytotoxicity in that the expression of the fusion protein does not modify the sensitivity of U937 cells to Fasmediated apoptosis. RA treatment, that is known to induce a degradation of PML/RARa protein, abolished the protective effect of PML/RARa against TNF mediated cytotoxicity. TNFR-I and TNFR-II quantification by flow cytometry showed that PML/RARa induced a significant downmodulation of both receptors, thus suggesting that the reduced sensitivity to TNFa mediated cytotoxicity may be related, at least in part, to a decreased receptor expression. Furthermore, additional studies have indicated that wt NB4 APL cell line, which synthesizes PML/RARa protein, is resistant to TNF mediated cytotoxicity, whereas a NB4 subclone (NB4.306), which had lost the capacity to synthesize PML/RARa protein, is sensitive to TNF mediated apoptosis. In conclusion, our results indicate that PML/RARa protects APL cells against TNF triggered cytotoxicity and this phenomenon may contribute to the survival advantage displayed by APL cells.

Original languageEnglish
Pages (from-to)789
Number of pages1
JournalExperimental Hematology
Volume25
Issue number8
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

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    Testa, U., Grianoni, F., Samoggia, P., Masciulli, R., Zanetti, C., Riccioni, R., Gambacorti Passerini, C., Grell, M., Pelicci, P. G., & Peschle, C. (1997). The acute promyelocytic leukemia-specific PML/RARa fusion protein reduces sensitivity to apoptosis upon tnfot stimulation. Experimental Hematology, 25(8), 789.