Switching leukemia cell phenotype between life and death

S.J. Tucker, C. Rae, A.F. Littlejohn, A. Paul, D.J. MacEwan

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor α, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte–macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-κB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-κB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-κB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.
LanguageEnglish
Pages12940-12945
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume101
Issue number35
DOIs
Publication statusPublished - 2004

Fingerprint

Leukemia
Phenotype
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Tumor Necrosis Factor-alpha
Myeloid Progenitor Cells
Cell Death
CASP8 and FADD-Like Apoptosis Regulating Protein
Receptor-Interacting Protein Serine-Threonine Kinases
Receptors, Tumor Necrosis Factor, Type II
Receptors, Tumor Necrosis Factor, Type I
Sodium Salicylate
Leukemia, Erythroblastic, Acute
K562 Cells
Caspase 8
Mitogen-Activated Protein Kinase Kinases
Granulocyte-Macrophage Colony-Stimulating Factor
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Caspases
Proteolysis

Keywords

  • leukemia cells
  • leukemia cell phenotype

Cite this

Tucker, S.J. ; Rae, C. ; Littlejohn, A.F. ; Paul, A. ; MacEwan, D.J. / Switching leukemia cell phenotype between life and death. In: Proceedings of the National Academy of Sciences . 2004 ; Vol. 101, No. 35. pp. 12940-12945.
@article{5b175cdabf1e4f199af859c6ad49eb08,
title = "Switching leukemia cell phenotype between life and death",
abstract = "Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor α, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte–macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-κB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-κB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-κB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.",
keywords = "leukemia cells, leukemia cell phenotype",
author = "S.J. Tucker and C. Rae and A.F. Littlejohn and A. Paul and D.J. MacEwan",
year = "2004",
doi = "10.1073/pnas.0400949101",
language = "English",
volume = "101",
pages = "12940--12945",
journal = "Proceedings of the National Academy of Sciences",
issn = "1091-6490",
number = "35",

}

Switching leukemia cell phenotype between life and death. / Tucker, S.J.; Rae, C.; Littlejohn, A.F.; Paul, A.; MacEwan, D.J.

In: Proceedings of the National Academy of Sciences , Vol. 101, No. 35, 2004, p. 12940-12945.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Switching leukemia cell phenotype between life and death

AU - Tucker, S.J.

AU - Rae, C.

AU - Littlejohn, A.F.

AU - Paul, A.

AU - MacEwan, D.J.

PY - 2004

Y1 - 2004

N2 - Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor α, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte–macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-κB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-κB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-κB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.

AB - Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor α, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte–macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-κB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-κB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-κB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.

KW - leukemia cells

KW - leukemia cell phenotype

U2 - 10.1073/pnas.0400949101

DO - 10.1073/pnas.0400949101

M3 - Article

VL - 101

SP - 12940

EP - 12945

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 35

ER -