Regulation of CD95 expression and CD95-mediated cell death by interferon-γ in acute lymphoblastic leukemia with chromosomal translocation t(4;11)

J. Dörrie, W. Schuh, A. Keil, E. Bongards, J. Greil, G. H. Fey, S. J. Zunino

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The regulatory effects of IFNγ on CD95 expression and CD95-mediated cell death were investigated in three high-risk pro-B acute lymphoblastic leukemia (ALL) lines that carry the chromosomal translocation t(4;11)(q21;q23). These leukemias are characteristically refractory to conventional chemotherapeutic treatments operating through the induction of apoptosis. However, the mechanisms leading to increased cell survival and resistance to cell death in these leukemias are largely unknown. Interferon-γ (IFNγ), a potent inhibitor of hematopoiesis, acts in part by upregulating CD95 and sensitizing cells to CD95-induced apoptosis. The t(4;11) lines SEM, RS4;11, and MV4;11 expressed low levels of CD95, but were completely resistant to CD95-mediated death. Addition of IFNγ markedly upregulated CD95 expression in SEM (8-9-fold), RS4;11 (2-3-fold), and MV4;11 (2-3-fold) lines. However, after treatment with IFNγ, only an 11% increase in sensitivity to CD95-mediated cell death was observed in SEM cells, whereas RS4;11 and MV4;11 cells remained resistant. Cycloheximide, but not actinomycin D or brefeldin A, increased CD95-specific cell death only in IFNγ-treated RS4;11 cells by approximately 12%. Abundant levels of Bcl-2 and Bcl-XL, known to inhibit CD95-signaling in some cells, were present suggesting a possible role for both molecules in the resistance to CD95-mediated cell death. Resistance of the leukemic blasts to CD95-mediated cell death and the failure of IFNγ to substantially sensitize the CD95-signaling pathway may contribute to the highly malignant phenotype of pro-B ALL with translocation t(4;11).

Original languageEnglish (US)
Pages (from-to)1539-1547
Number of pages9
JournalLeukemia
Volume13
Issue number10
StatePublished - 1999
Externally publishedYes

Fingerprint

Genetic Translocation
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Interferons
Cell Death
Leukemia
Apoptosis
Brefeldin A
Hematopoiesis
Dactinomycin
Cycloheximide
Cell Survival
Phenotype

Keywords

  • Acute lymphoblastic leukemia
  • Apoptosis
  • CD95-mediated death
  • Interferon-γ
  • Translocation t(4;11)

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Dörrie, J., Schuh, W., Keil, A., Bongards, E., Greil, J., Fey, G. H., & Zunino, S. J. (1999). Regulation of CD95 expression and CD95-mediated cell death by interferon-γ in acute lymphoblastic leukemia with chromosomal translocation t(4;11). Leukemia, 13(10), 1539-1547.

Regulation of CD95 expression and CD95-mediated cell death by interferon-γ in acute lymphoblastic leukemia with chromosomal translocation t(4;11). / Dörrie, J.; Schuh, W.; Keil, A.; Bongards, E.; Greil, J.; Fey, G. H.; Zunino, S. J.

In: Leukemia, Vol. 13, No. 10, 1999, p. 1539-1547.

Research output: Contribution to journalArticle

Dörrie, J, Schuh, W, Keil, A, Bongards, E, Greil, J, Fey, GH & Zunino, SJ 1999, 'Regulation of CD95 expression and CD95-mediated cell death by interferon-γ in acute lymphoblastic leukemia with chromosomal translocation t(4;11)', Leukemia, vol. 13, no. 10, pp. 1539-1547.
Dörrie, J. ; Schuh, W. ; Keil, A. ; Bongards, E. ; Greil, J. ; Fey, G. H. ; Zunino, S. J. / Regulation of CD95 expression and CD95-mediated cell death by interferon-γ in acute lymphoblastic leukemia with chromosomal translocation t(4;11). In: Leukemia. 1999 ; Vol. 13, No. 10. pp. 1539-1547.
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abstract = "The regulatory effects of IFNγ on CD95 expression and CD95-mediated cell death were investigated in three high-risk pro-B acute lymphoblastic leukemia (ALL) lines that carry the chromosomal translocation t(4;11)(q21;q23). These leukemias are characteristically refractory to conventional chemotherapeutic treatments operating through the induction of apoptosis. However, the mechanisms leading to increased cell survival and resistance to cell death in these leukemias are largely unknown. Interferon-γ (IFNγ), a potent inhibitor of hematopoiesis, acts in part by upregulating CD95 and sensitizing cells to CD95-induced apoptosis. The t(4;11) lines SEM, RS4;11, and MV4;11 expressed low levels of CD95, but were completely resistant to CD95-mediated death. Addition of IFNγ markedly upregulated CD95 expression in SEM (8-9-fold), RS4;11 (2-3-fold), and MV4;11 (2-3-fold) lines. However, after treatment with IFNγ, only an 11{\%} increase in sensitivity to CD95-mediated cell death was observed in SEM cells, whereas RS4;11 and MV4;11 cells remained resistant. Cycloheximide, but not actinomycin D or brefeldin A, increased CD95-specific cell death only in IFNγ-treated RS4;11 cells by approximately 12{\%}. Abundant levels of Bcl-2 and Bcl-XL, known to inhibit CD95-signaling in some cells, were present suggesting a possible role for both molecules in the resistance to CD95-mediated cell death. Resistance of the leukemic blasts to CD95-mediated cell death and the failure of IFNγ to substantially sensitize the CD95-signaling pathway may contribute to the highly malignant phenotype of pro-B ALL with translocation t(4;11).",
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AU - Greil, J.

AU - Fey, G. H.

AU - Zunino, S. J.

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AB - The regulatory effects of IFNγ on CD95 expression and CD95-mediated cell death were investigated in three high-risk pro-B acute lymphoblastic leukemia (ALL) lines that carry the chromosomal translocation t(4;11)(q21;q23). These leukemias are characteristically refractory to conventional chemotherapeutic treatments operating through the induction of apoptosis. However, the mechanisms leading to increased cell survival and resistance to cell death in these leukemias are largely unknown. Interferon-γ (IFNγ), a potent inhibitor of hematopoiesis, acts in part by upregulating CD95 and sensitizing cells to CD95-induced apoptosis. The t(4;11) lines SEM, RS4;11, and MV4;11 expressed low levels of CD95, but were completely resistant to CD95-mediated death. Addition of IFNγ markedly upregulated CD95 expression in SEM (8-9-fold), RS4;11 (2-3-fold), and MV4;11 (2-3-fold) lines. However, after treatment with IFNγ, only an 11% increase in sensitivity to CD95-mediated cell death was observed in SEM cells, whereas RS4;11 and MV4;11 cells remained resistant. Cycloheximide, but not actinomycin D or brefeldin A, increased CD95-specific cell death only in IFNγ-treated RS4;11 cells by approximately 12%. Abundant levels of Bcl-2 and Bcl-XL, known to inhibit CD95-signaling in some cells, were present suggesting a possible role for both molecules in the resistance to CD95-mediated cell death. Resistance of the leukemic blasts to CD95-mediated cell death and the failure of IFNγ to substantially sensitize the CD95-signaling pathway may contribute to the highly malignant phenotype of pro-B ALL with translocation t(4;11).

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