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

Published

Journal Article

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) pi, 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.

Full Text

Duke Authors

Cited Authors

  • Cripe, LD; Gelfanov, VM; Smith, EA; Spigel, DR; Phillips, CA; Gabig, TG; Jung, S-H; Fyffe, J; Hartman, AD; Kneebone, P; Mercola, D; Burgess, GS; Boswell, HS

Published Date

  • May 2002

Published In

Volume / Issue

  • 16 / 5

Start / End Page

  • 799 - 812

PubMed ID

  • 11986940

Pubmed Central ID

  • 11986940

International Standard Serial Number (ISSN)

  • 0887-6924

Digital Object Identifier (DOI)

  • 10.1038/sj.leu.2402457

Language

  • eng

Conference Location

  • England