T-lineage ALL is an unfavorable subtype of childhood ALL and is associated with in-vitro resistance to drugs. Therefore the identification of novel genes that may serve as targets to modulate drug resistance is desirable. We compared the gene expression profile of 28 pediatric T-ALL patients being either sensitive (DNRS) or resistant (DNRR) to daunorubicin. The aryl hydrocarbon receptor (AHR) gene appeared to be highly discriminating between DNRS and DNRR T-ALL patients. AHR is known to mediate signal transduction in response to xenobiotics by activating the transcription of xenobiotic-responsive genes such as CYP1A1 and CYP1A2. Expression analysis by real-time quantitative PCR confirmed that basal AHR mRNA levels in ALL cells derived from patients is correlated with DNR resistance (Rs=0.41, P=0.02). Exposure to DNR of the REH cell line expressing a low AHR level led to a 40-fold induction of AHR mRNA. In two other cell lines (i.e. HL60 and SEMK-2) expressing high levels of AHR the upregulation was only 1.4-fold. In REH, the 40-fold induction of AHR after DNR exposure was inhibited by 40% after pre-exposure to the AHR inhibitors salicylamide (SAL) and geldanamycin (GA). Pre-incubation of leukemic cells of T-ALL patients with SAL or GA prior to DNR exposure had a synergistic effect on DNR sensitivity. In addition, transfection of SEMK-2 cells with AHR-specific siRNA resulted in the reduction of AHR expression by 80% after 24 h and had also a synergistic effect on DNR induced cell kill up to 96 hours after siRNA treatment. We conclude that a high expression of the AHR gene is involved in DNR resistance in childhood T-ALL and that AHR may serve as a very attractive new therapeutic target.