Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib

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Abstract

Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30\% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such approaches.
Original languageEnglish
Pages (from-to)741-750
Number of pages10
JournalOncology Reports
Volume29
Issue number2
DOIs
Publication statusPublished - Feb 2013

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RNA Stability
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Pharmaceutical Preparations
Genes
Therapeutics
Imatinib Mesylate
Bone Marrow
Genotype
Messenger RNA

Keywords

    Cite this

    @article{b9f02a64897b4abcb32a0beef133f7d8,
    title = "Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib",
    abstract = "Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30\{\%} of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such approaches.",
    keywords = "MOLECULAR RESPONSES, BCR-ABL1, ABCG2, KINASE DOMAIN MUTATIONS, drug resistance, MVP, FUSION GENE TRANSCRIPTS, STANDARD-DOSE IMATINIB, EUROPEAN LEUKEMIANET, tyrosine kinase inhibitors, drug transporters, SLC22A1, chronic myeloid leukemia, LOW OCT-1 ACTIVITY, SUBOPTIMAL RESPONSE, P-GLYCOPROTEIN, MULTIDRUG-RESISTANCE, ABCC1, imatinib, ABCB1, BINDING-CASSETTE TRANSPORTERS",
    author = "Marta Gromicho and Fernandes, {Maria Alexandra N{\'u}ncio de Carvalho Ramos} and Jos{\'e} Rueff and Rodrigues, {Ant{\'o}nio S}",
    year = "2013",
    month = "2",
    doi = "10.3892/or.2012.2153",
    language = "English",
    volume = "29",
    pages = "741--750",
    journal = "Oncology Reports",
    issn = "1021-335X",
    publisher = "Spandidos Publications",
    number = "2",

    }

    TY - JOUR

    T1 - Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib

    AU - Gromicho, Marta

    AU - Fernandes, Maria Alexandra Núncio de Carvalho Ramos

    AU - Rueff, José

    AU - Rodrigues, António S

    PY - 2013/2

    Y1 - 2013/2

    N2 - Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30\% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such approaches.

    AB - Despite the success of imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), approximately 30\% of patients are resistant to therapy, mostly due to unknown causes. To profile the expression signatures of drug transporters throughout IM therapy and correlate them with resistance, we quantified mRNA expression levels of the SLC22A12, ABCB1, ABCC1, ABCG2 and MVP genes in consecutive samples from peripheral blood or bone marrow of CML patients who were either responsive or resistant to IM. Additionally we identified and quantified BCR-ABL1 transcript variants and analyzed 1236T>C ABCB1 and 480G>C SLC22A1 polymorphisms. A relationship between the type of BCR-ABL1 transcript or ABCB1 or SLC22A1 genotype and response to treatment was not discovered. However, the studied genes had higher expression levels in follow-up compared to the diagnostic samples, demonstrating a possible induction in expression. IM-sensitive patients presented significantly higher values of SLC22A1 expression, suggesting higher drug influx. Most importantly, while responding patients demonstrated stable expression signatures in consecutive samples, there was considerable variation in IM-resistant patients, indicating that single point sampling expression signatures are not reliable in predicting clinical outcomes or prognostic features in these patients. Studies that assessed consecutive samples from CML patients in order to evaluate the variation in expression levels of transporter genes are limited yet our study emphasizes the importance of such approaches.

    KW - MOLECULAR RESPONSES

    KW - BCR-ABL1

    KW - ABCG2

    KW - KINASE DOMAIN MUTATIONS

    KW - drug resistance

    KW - MVP

    KW - FUSION GENE TRANSCRIPTS

    KW - STANDARD-DOSE IMATINIB

    KW - EUROPEAN LEUKEMIANET

    KW - tyrosine kinase inhibitors

    KW - drug transporters

    KW - SLC22A1

    KW - chronic myeloid leukemia

    KW - LOW OCT-1 ACTIVITY

    KW - SUBOPTIMAL RESPONSE

    KW - P-GLYCOPROTEIN

    KW - MULTIDRUG-RESISTANCE

    KW - ABCC1

    KW - imatinib

    KW - ABCB1

    KW - BINDING-CASSETTE TRANSPORTERS

    U2 - 10.3892/or.2012.2153

    DO - 10.3892/or.2012.2153

    M3 - Article

    VL - 29

    SP - 741

    EP - 750

    JO - Oncology Reports

    JF - Oncology Reports

    SN - 1021-335X

    IS - 2

    ER -