Multidrug resistance in leukemia has been attributed to expression of the p-glycoprotein, product of the mdrl gene, or to high expression of bcl-2, an anti-apoptotic effector protein. However, expression of these two effectors is highly restricted within certain leukcmic FAB types, and their frequency does not adequately explain many cases of treatment failure. We hypothesized that failure of induction therapy with cytosine arabinoside plus anthracycline may more commonly follow glutathione (GSH)-dependent drug export by the multidrug resistance-related protein (MRP), and that MRP expression, expression of enzymes such as glutathione-S-transferase, and also the rate-limiting enzyme for GSH synthesis (GGCS), may be coordinately induced in leukemia by high activity of the jun-N-terminal kinase (INK). JNK regulates by posttranslational modification on the c-jun protein, c-jun/AP-1 transactivation of the c-jun, G-S-transferase, and possibly MRP and GGCS, gene(s) in a positive autoregulatory loop. We analyzed JNK kinase activity from cell lysates on GST-c-jun substrate followed by SDS-PAGE and autoradiography as well as c-jun protein expresssion by immunoblot. We compared these activities with expression levels of mRNA for MRP and mdrl, determined by semiquantitative RT-PCR, within 15 cases of acute leukemia (12 ANLL, 3 CML BC). Six cases were secondary or relapsed leukemia. JNK activity assay was positive in 8 of 13 cases tested. Of these, six were the secondary or relapsed disease specimens. High levels of MRP mRNA was noted in 7/11 of cases subjected to analysis, and there was agreement with JNK activity status in 7/11 cases overall. All secondary/relapsed leukemias tested in both assays demonstrated JNK activity and MRP expression except one, whose JNK kinase activity was absent, but cellular c-jun protein was present. This experience suggests there is a functional link between JNK/c-jun expression and associated treatment failure of high-risk leukemias that are induced to express MRP. It is tempting to postulate that c-jun/AP-1-mediated transcriptional activation of MRP gene expression, and augmented synthesis of GSH driven by AP-1-dependent GGCS, is a dominant cause of treatment failure in acute leukemia, especially in a significant proportion of cases that fail to express measurable mdr1.
|Original language||English (US)|
|Number of pages||1|
|State||Published - Dec 1 1997|
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
- Cancer Research