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

L D Cripe1, V M Gelfanov, E A Smith

  • 1Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 1044 W Walnut Street, Indianapolis, IN 46202, USA.

Leukemia
|May 3, 2002
PubMed

Insights

Constitutive activity of c-jun-N-terminal kinase (JNK) predicts treatment failure in acute myeloid leukemia (AML). Targeting JNK and c-jun may overcome multidrug resistance in AML.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Constitutive activity of leukemic cell c-jun-N-terminal kinase (JNK) is linked to treatment failure in acute myeloid leukemia (AML).
  • The mechanistic basis for this association requires elucidation.
  • Multidrug resistance (MDR) is a significant challenge in AML therapy.

Purpose of the Study:

  • To investigate the mechanistic origins of the association between JNK activity and treatment failure in AML.
  • To explore the role of c-jun/AP-1 signaling in multidrug resistance and cellular homeostasis in AML.
  • To evaluate JNK and c-jun as potential therapeutic targets in MDR AML.

Main Methods:

  • Transfection of a multidrug resistant leukemic cell line (HL-60/ADR) with a dominant-negative c-jun vector.
  • Analysis of gene expression, including c-jun/AP-1-dependent genes like catalase and glutathione-S-transferase (GST) pi.
  • Assessment of multidrug resistance protein 1 (MRP1) efflux and cellular sensitivity to daunorubicin.
  • Biochemical analysis of c-jun expression, JNK activity, hyperleukocytosis, and MRP efflux in primary adult AML samples.

Main Results:

  • Down-regulation of c-jun/AP-1-dependent genes involved in cellular homeostasis was observed after c-jun transfection.
  • Abrogation of MRP efflux and increased sensitivity to daunorubicin occurred in HL-60/ADR cells with dominant-negative c-jun.
  • A statistical correlation was found between c-jun expression, JNK activity, hyperleukocytosis, and MRP efflux in primary AML samples.
  • Loss of MRP1 protein expression correlated with abrogation of MRP efflux.

Conclusions:

  • c-jun/AP-1 signaling and its regulatory kinase JNK play a survival role in AML, particularly in response to oxidative stress and in the function of ATP-binding cassette efflux pumps.
  • These findings suggest an evolutionary conservation of this function.
  • JNK and c-jun represent promising therapeutic targets for overcoming multidrug resistance in AML.

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