Chronic Myeloid Leukemia Patients Sensitive and Resistant to Imatinib Treatment Show Different Metabolic Responses.

The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML). However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP array analysis, karyotype and mutation of Abl kinase domain, the metabolic phenotypes and genomic polymorphisms of CML patients and their diverse responses to imatinib were characterized.

We identified 26 untreated CML patients (UCML), 33 patients treated with imatinib at daily doses of 300–800 mg, and 18 healthy volunteers. 14 patients were resistant to imatinib. Routine cytogenetic analysis was performed in patients. In the resistant patients, ABL kinase domain mutations were detected. High-quality genomic DNA was processed in accordance with the genomic mapping 250K NspI protocol and hybridized to 250K NspI SNP arrays according to the manufacturer's instructions in 9 patients treated with imatinib. Gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) was utilized for the measurement of the small molecular weight endogenous compounds. The metabolic phenotypes of CML patients, and the responses of CML to imatinib were characterized by means of GC/TOFMS based metabonomic technique.

Mutations were detected in only 1 BC patient (L232P, F336L, and C349R). A total of 44 deletions, 2 duplication, and 7 regions of loss of heterozygosity (LOH) were identified by SNP array analysis. In addition to sex chromosome, four of 6 CP RCML patients did not show other abnormal genome. Deletions, duplication and LOH on chromosome 17, 9, 22, 5 and 19 were identified in several important chromosomal regions of BC patients. The untreated CML patients (UCML) showed different metabolic pattern from those of healthy controls, and the discriminatory metabolites suggested the perturbed metabolism of the urea cycle, tricarboxylic acid cycle, lipid metabolism, and amino acid turnover in UCML. Some amino acids, such as glutamate, ornithine, glycine, and pyroglutamate, were found at higher levels in UCML compared with those in HC, which indicates a cellular requirement for a higher turnover of structural proteins. After imatinib treatment, patients sensitive to imatinib (SCML) and patients resistant to imatinib (RCML) had similar metabolic phenotypes to those of healthy controls and UCML, respectively. SCML showed a significant metabolic response to imatinib, with marked restoration of the perturbed metabolism. Most of the metabolites characterizing CML were adjusted to normal levels, including the intermediates of the urea cycle and tricarboxylic acid cycle (TCA). In contrast, neither cytogenetic nor metabonomic analysis indicated any positive response to imatinib in RCML. Taken together, it strongly suggested that metabolic variation between BC and CP patients were closely related to genomic alterations.

We report for the first time the associated genetic and metabonomic responses of CML patients to imatinib and show that the perturbed in vivo metabolism of UCML is independent of imatinib treatment in resistant patients. Thus, metabonomics can potentially characterize patients sensitivity or resistance to drug intervention.

No relevant conflicts of interest to declare.