Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): Signaling to multidrug-efflux and hyperproliferation

Larry Cripe, V. M. Gelfanov, E. A. Smith, D. R. Spigel, C. A. Phillips, T. G. Gabig, S. H. Jung, Joanne Daggy, A. D. Hartman, P. Kneebone, D. Mercola, G. S. Burgess, H. Boswell

Research output: Contribution to journalArticle

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Abstract

A relationship was proved between constitutive activity of leukemic cell c-jun-N-terminal kinase (JNK) and treatment failure in AML. Specifically, early treatment failure was predicted by the presence of constitutive JNK activity. The mechanistic origins of this association was sought. A multidrug resistant leukemic cell line, HL-60/ADR, characterized by hyperexpression of c-jun and JNK activity, was transfected with a mutant c-jun vector, whose substrate N-terminal c-jun serines were mutated. Down-regulated expression occurred of c-jun/AP-1-dependent genes, catalase and glutathione-S-transferase (GST) π, which participate in cellular homeostasis to oxidative stress and xenobiotic exposure. MRP-efflux was abrogated in HL-60/ADR cells with dominant-negative c-jun, perhaps because MRP1 protein expression was also lost. Heightened sensitivity to daunorubicin resulted in cells subjected to this change. Biochemical analysis in 67 primary adult AML samples established a statistical correlation between cellular expression of c-jun and JNK activity, JNK activity with hyperleukocytosis at presentation of disease, and with exuberant MRP efflux. These findings reflect the survival role for c-jun/AP-1 and its regulatory kinase previously demonstrated for yeast in homeostatic response to oxidative stress and in operation of ATP-binding cassette efflux pumps, and may support evolutionary conservation of such function. Thus, JNK and c-jun may be salient drug targets in multidrug resistant AML.

Original languageEnglish
Pages (from-to)799-812
Number of pages14
JournalLeukemia
Volume16
Issue number5
DOIs
StatePublished - 2002

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JNK Mitogen-Activated Protein Kinases
Acute Myeloid Leukemia
Transcription Factor AP-1
Treatment Failure
Oxidative Stress
Daunorubicin
HL-60 Cells
Xenobiotics
Glutathione Transferase
Catalase
Serine
Homeostasis
Phosphotransferases
Adenosine Triphosphate
Yeasts
Cell Line
Pharmaceutical Preparations
Genes
Proteins

Keywords

  • AML
  • Multidrug resistance
  • Signaling

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML) : Signaling to multidrug-efflux and hyperproliferation. / Cripe, Larry; Gelfanov, V. M.; Smith, E. A.; Spigel, D. R.; Phillips, C. A.; Gabig, T. G.; Jung, S. H.; Daggy, Joanne; Hartman, A. D.; Kneebone, P.; Mercola, D.; Burgess, G. S.; Boswell, H.

In: Leukemia, Vol. 16, No. 5, 2002, p. 799-812.

Research output: Contribution to journalArticle

Cripe, L, Gelfanov, VM, Smith, EA, Spigel, DR, Phillips, CA, Gabig, TG, Jung, SH, Daggy, J, Hartman, AD, Kneebone, P, Mercola, D, Burgess, GS & Boswell, H 2002, 'Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): Signaling to multidrug-efflux and hyperproliferation', Leukemia, vol. 16, no. 5, pp. 799-812. https://doi.org/10.1038/sj.leu.2402457
Cripe, Larry ; Gelfanov, V. M. ; Smith, E. A. ; Spigel, D. R. ; Phillips, C. A. ; Gabig, T. G. ; Jung, S. H. ; Daggy, Joanne ; Hartman, A. D. ; Kneebone, P. ; Mercola, D. ; Burgess, G. S. ; Boswell, H. / Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML) : Signaling to multidrug-efflux and hyperproliferation. In: Leukemia. 2002 ; Vol. 16, No. 5. pp. 799-812.
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AU - Smith, E. A.

AU - Spigel, D. R.

AU - Phillips, C. A.

AU - Gabig, T. G.

AU - Jung, S. H.

AU - Daggy, Joanne

AU - Hartman, A. D.

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