The PML/RARα fusion protein inhibits tumor necrosis factor-α-induced apoptosis in U937 cells and acute promyelocytic leukemia blasts

Ugo Testa, Francesco Grignani, Paola Samoggia, Cristiana Zanetti, Roberta Riccioni, Francesco Lo Coco, Daniela Diverio, Nadia Felli, Carlo Gambacorti Passerini, Matthias Grell, Pier Giuseppe Pelicci, Cesare Peschle

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Abstract

We investigated the effect of the acute promyelocytic leukemia (APL) specific PML/RARα fusion protein on the sensitivity to TNF-α-mediated apoptosis. The U937 leukemia cell line was transduced with PML/RARα cDNA. PML/RARα expression caused a markedly reduced sensitivity to TNF-α, even if apoptosis was triggered by agonistic antibodies to TNF-α receptors I and II (TNF-αRI, II). PML/RARα induced a 10-20-fold decrease of the TNF-α- binding capacity via downmodulation of both TNF-αRI and TNF-αRII: this may mediate at least in part the reduced sensitivity to TNF-α. Furthermore, the fusion protein did not modify Fas expression (CD95) or sensitivity to Fas- mediated apoptosis. The pathophysiological significance of these findings is supported by two series of observations. (a) Fresh APL blasts exhibit no TNF- α binding and are resistant to TNFα-mediated apoptosis. Conversely, normal myeloblasts-pro-myelocytes show marked TNF-αR expression and are moderately sensitive to TNF-α-mediated cytotoxicity. Similarly, blasts from other types of acute myeloid leukemia (AML M1, M2, and M4 FAB types) show an elevated TNF-α binding. (b) The NB4 APL cell line, which is PML/RARα+, shows low TNF-αR expression capacity and is resistant to TNF-α-triggered apoptosis; conversely a PML/RARα-NB4 subclone (NB4.306) exhibits detectable TNF-α- binding capacity and is sensitive to TNF-α-mediated cytotoxicity. These studies indicate that the PML/RARα fusion protein protects against TNF-α- induced apoptosis, at least in part via downmodulation of TNF-αRI/II: this phenomenon may play a significant role in APL, which is characterized by prolonged survival of leukemic blasts.

Original languageEnglish
Pages (from-to)2278-2289
Number of pages12
JournalJournal of Clinical Investigation
Volume101
Issue number10
Publication statusPublished - May 15 1998

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U937 Cells
Acute Promyelocytic Leukemia
Tumor Necrosis Factor-alpha
Apoptosis
Granulocyte Precursor Cells
Proteins
Receptors, Tumor Necrosis Factor, Type II
Cell Line
Tumor Necrosis Factor Receptors
Acute Myeloid Leukemia
Leukemia
Complementary DNA
Antibodies

Keywords

  • Apoptosis
  • Fusion protein
  • Leukemia
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Medicine(all)

Cite this

The PML/RARα fusion protein inhibits tumor necrosis factor-α-induced apoptosis in U937 cells and acute promyelocytic leukemia blasts. / Testa, Ugo; Grignani, Francesco; Samoggia, Paola; Zanetti, Cristiana; Riccioni, Roberta; Lo Coco, Francesco; Diverio, Daniela; Felli, Nadia; Passerini, Carlo Gambacorti; Grell, Matthias; Pelicci, Pier Giuseppe; Peschle, Cesare.

In: Journal of Clinical Investigation, Vol. 101, No. 10, 15.05.1998, p. 2278-2289.

Research output: Contribution to journalArticle

Testa, U, Grignani, F, Samoggia, P, Zanetti, C, Riccioni, R, Lo Coco, F, Diverio, D, Felli, N, Passerini, CG, Grell, M, Pelicci, PG & Peschle, C 1998, 'The PML/RARα fusion protein inhibits tumor necrosis factor-α-induced apoptosis in U937 cells and acute promyelocytic leukemia blasts', Journal of Clinical Investigation, vol. 101, no. 10, pp. 2278-2289.
Testa, Ugo ; Grignani, Francesco ; Samoggia, Paola ; Zanetti, Cristiana ; Riccioni, Roberta ; Lo Coco, Francesco ; Diverio, Daniela ; Felli, Nadia ; Passerini, Carlo Gambacorti ; Grell, Matthias ; Pelicci, Pier Giuseppe ; Peschle, Cesare. / The PML/RARα fusion protein inhibits tumor necrosis factor-α-induced apoptosis in U937 cells and acute promyelocytic leukemia blasts. In: Journal of Clinical Investigation. 1998 ; Vol. 101, No. 10. pp. 2278-2289.
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abstract = "We investigated the effect of the acute promyelocytic leukemia (APL) specific PML/RARα fusion protein on the sensitivity to TNF-α-mediated apoptosis. The U937 leukemia cell line was transduced with PML/RARα cDNA. PML/RARα expression caused a markedly reduced sensitivity to TNF-α, even if apoptosis was triggered by agonistic antibodies to TNF-α receptors I and II (TNF-αRI, II). PML/RARα induced a 10-20-fold decrease of the TNF-α- binding capacity via downmodulation of both TNF-αRI and TNF-αRII: this may mediate at least in part the reduced sensitivity to TNF-α. Furthermore, the fusion protein did not modify Fas expression (CD95) or sensitivity to Fas- mediated apoptosis. The pathophysiological significance of these findings is supported by two series of observations. (a) Fresh APL blasts exhibit no TNF- α binding and are resistant to TNFα-mediated apoptosis. Conversely, normal myeloblasts-pro-myelocytes show marked TNF-αR expression and are moderately sensitive to TNF-α-mediated cytotoxicity. Similarly, blasts from other types of acute myeloid leukemia (AML M1, M2, and M4 FAB types) show an elevated TNF-α binding. (b) The NB4 APL cell line, which is PML/RARα+, shows low TNF-αR expression capacity and is resistant to TNF-α-triggered apoptosis; conversely a PML/RARα-NB4 subclone (NB4.306) exhibits detectable TNF-α- binding capacity and is sensitive to TNF-α-mediated cytotoxicity. These studies indicate that the PML/RARα fusion protein protects against TNF-α- induced apoptosis, at least in part via downmodulation of TNF-αRI/II: this phenomenon may play a significant role in APL, which is characterized by prolonged survival of leukemic blasts.",
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AU - Zanetti, Cristiana

AU - Riccioni, Roberta

AU - Lo Coco, Francesco

AU - Diverio, Daniela

AU - Felli, Nadia

AU - Passerini, Carlo Gambacorti

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AU - Pelicci, Pier Giuseppe

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