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High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients.

ABSTRACT: Pharmacogenetic studies in chronic myelogenous leukemia (CML) typically use a candidate gene approach. In an alternative strategy, we analyzed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using a DNA chip containing 857 SNPs covering 94 drug transporter genes. Two cohorts of CML patients treated with imatinib were evaluated: an exploratory cohort including 105 patients treated at 400 mg/d and a validation cohort including patients sampled from the 400 mg/d and 600 mg/d arms of the prospective SPIRIT trial (n=239). Twelve SNPs discriminating patients according to cumulative incidence of major molecular response (CI-MMR) were identified within the exploratory cohort. Three of them, all located within the ABCG2 gene, were validated in patients included in the 400 mg/d arm of the SPIRIT trial. We identified an ABCG2 haplotype (define as G-G, rs12505410 and rs2725252) as associated with significantly higher CI-MMR in patients treated at 400 mg/d. Interestingly, we found that patients carrying this ABCG2 "favorable" haplotype in the 400 mg arm reached similar CI-MMR rates that patients randomized in the imatinib 600 mg/d arm. Our results suggest that response to imatinib may be influenced by constitutive haplotypes in drug transporter genes. Lower response rates associated with "non- favorable" ABCG2 haplotypes may be overcome by increasing the imatinib daily dose up to 600 mg/d.

SUBMITTER: Delord M

PROVIDER: S-EPMC3858547 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients.

Delord Marc M Rousselot Philippe P Cayuela Jean Michel JM Sigaux François F Guilhot Joëlle J Preudhomme Claude C Guilhot François F Loiseau Pascale P Raffoux Emmanuel E Geromin Daniela D Génin Emmanuelle E Calvo Fabien F Bruzzoni-Giovanelli Heriberto H

Oncotarget 20131001 10

Pharmacogenetic studies in chronic myelogenous leukemia (CML) typically use a candidate gene approach. In an alternative strategy, we analyzed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using a DNA chip containing 857 SNPs covering 94 drug transporter genes. Two cohorts of CML patients treated with imatinib were evaluated: an exploratory cohort including 105 patients treated at 400 mg/d and a validation cohort including p ...[more]

PMID: 24123600

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Project description:Chronic myelogenous leukemia (CML) is maintained by a minor population of leukemic stem cells (LSCs) that exhibit innate resistance to tyrosine kinase inhibitors (TKIs) targeting BCR-ABL. Innate resistance can be induced by secreted bone marrow stromal cytokines and growth factors (BMSFs) that protect CML-LSCs from TKIs, resulting in minimal residual disease. Developing strategies to eradicate innate TKI resistance in LSCs is critical for preventing disease relapse. Cancer cells balance reactive oxygen species (ROS) at higher than normal levels, promoting their proliferation and survival, but also making them susceptible to damage by ROS-generating agents. Bcr-Abl increases cellular ROS levels, which can be reduced with TKI inhibitors, whereas, BMSFs increase ROS levels. We hypothesized that BMSF-mediated increases in ROS would trigger ROS damage in TKI-treated CML-LSCs when exposed to chaetocin, a mycotoxin that imposes oxidative stress by inhibiting thioredoxin reductase-1. Here, we showed that chaetocin suppressed viability and colony formation, and induced apoptosis of the murine hematopoietic cell line TonB210 with and without Bcr-Abl expression, and these effects were potentiated by BMSFs. In contrast, imatinib activities in Bcr-Abl-positive TonB210 cells were inhibited by BMSFs. Further, BMSFs did not inhibit imatinib activities when TonB210 cells expressing Bcr-Abl were cotreated with chaetocin. Chaetocin showed similar activities against LSC-enriched CML cell populations isolated from a murine transplant model of CML blast crisis that were phenotypically negative for lineage markers and positive for Sca-1 and c-Kit (CML-LSK). BMSFs and chaetocin increased ROS in CML-LSK cells and addition of BMSFs and chaetocin resulted in higher levels compared with chaetocin or BMSF treatment alone. Pretreatment of CML-LSKs with the antioxidant N-acetylcysteine blocked chaetocin cytotoxicity, even in the presence of BMSFs, demonstrating the importance ROS for chaetocin activities. Chaetocin effects on self-renewal of CML-LSKs were assessed by transplanting CML-LSKs into secondary recipients following ex vivo exposure to chaetocin, in the presence or absence of BMSFs. Disease latency in mice transplanted with CML-LSKs following chaetocin treatment more than doubled compared with untreated CML-LSKs or BMSFs-treated CML-LSKs. Mice transplanted with CML-LSKs following chaetocin treatment in the presence of BMSFs had significantly extended survival time compared with mice transplanted with CML-LSKs treated with chaetocin alone. Our findings indicate that chaetocin activity against CML-LSKs is significantly enhanced in the presence of BMSFs and suggest that chaetocin may be effective as a codrug to complement TKIs in CML treatment by disrupting the innate resistance of CML-LSKs through an ROS dependent mechanism.

Dataset Information

High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients.

Publications

High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients.

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