Individualized Multidrug Resistance In Acute Myeloid Leukemia

Abstract 2491

While much has been discovered in the laboratory regarding the mechanisms of multidrug resistance (MDR), based on phase III clinical trials of ATP-binding cassette (ABC) transporter modulators, these findings have not resulted in appreciable clinical benefit in acute myeloid leukemia (AML) patients. In this pilot study, we investigated the clinical relevance of 380 genes related to MDR in 31 samples from AML patients who had undergone conventional treatment, with 11 patients contributing samples at diagnosis and relapse, using TaqMan Low Density Arrays (TLDA). We and others have shown that the TaqMan-based qRT-PCR is superior to microarrays and SYBR-green-based qRT-PCR because of higher sensitivity and specificity in determining expression of highly homologous gene family members, such as the ABC transporters. 380 genes involved in metabolism, signal transduction, DNA repair, stress response, tumor suppressor activity, oncogenic transformation, apoptosis, and drug uptake or efflux were curated based on their potential role in MDR in the current literature. We found expression of four genes previously unreported in AML in both diagnostic and relapsed patient samples to correlate with duration of complete remission (CR) of induction chemotherapy: SLC7A8 and HSPE1 correlate negatively while GBP1 and ABCD2 correlate positively with CR duration (>2-fold change relative to the median, p<0.05). SLC7A8 is an L-type amino acid transporter that has not previously been found to be expressed in tumor cells, while GBP1 is a guanylate binding protein that might have antiproliferative and antiangiogenic effects. HSPE1 and ABCD2 are poorly characterized members of heat shock protein and ABC transporter families, respectively. NFKB1A, involved in the NFKB pathway, was found to correlate positively with CR duration in both samples at diagnosis and relapse (>2-fold change relative to the median, p<0.05). In a grouped comparison of all samples at relapse relative to diagnosis, GSTM5, a glutathione-S-transferase isoform involved in drug metabolism, was upregulated while TNF, tumor necrosis factor, was downregulated (>2 fold change compared to diagnosis, p<0.05). ABCB1, the best studied ABC transporter for which many modulators have been developed, was upregulated in some patients, while downregulated in others at relapse (>2 fold change compared to diagnosis, p<0.05). A patient-by-patient analysis of the paired samples revealed that each had a unique set of genes that was upregulated or downregulated at relapse relative to diagnosis, confirming the heterogeneity of AML with respect to acquired MDR. Finally, we assessed the ability of 15 cell lines to accurately depict MDR-linked gene expression in patients. The gene expression patterns of all cell lines were quite different from the patient samples, signifying the need to develop appropriate preclinical models for the study of MDR in AML.