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

Cite this

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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",
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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 -