DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells.

Joana Dinis, Vânia Silva, Marta Gromicho, Célia Martins, António Laires, P Tavares, Paula Rendeiro, Fátima Torres, J. Rueff, AS Rodrigues

Research output: Contribution to journalArticle

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Abstract

Abstract Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.
Original languageEnglish
Pages (from-to)2004-14
Number of pages11
JournalLeukemia & Lymphoma
Volume53
Issue number10
DOIs
Publication statusPublished - 2012

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K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
DNA Damage
DNA Repair
Protein-Tyrosine Kinases
Doxorubicin
Cell Survival
Genes
Blast Crisis
Camptothecin
Comet Assay
DNA
Small Interfering RNA
Imatinib Mesylate
Up-Regulation
Gene Expression
Drug Therapy
Messenger RNA
Therapeutics

Keywords

    Cite this

    Dinis, Joana ; Silva, Vânia ; Gromicho, Marta ; Martins, Célia ; Laires, António ; Tavares, P ; Rendeiro, Paula ; Torres, Fátima ; Rueff, J. ; Rodrigues, AS. / DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells. In: Leukemia & Lymphoma. 2012 ; Vol. 53, No. 10. pp. 2004-14.
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    abstract = "Abstract Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.",
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    DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells. / Dinis, Joana; Silva, Vânia; Gromicho, Marta ; Martins, Célia ; Laires, António ; Tavares, P; Rendeiro, Paula; Torres, Fátima ; Rueff, J.; Rodrigues, AS.

    In: Leukemia & Lymphoma, Vol. 53, No. 10, 2012, p. 2004-14.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells.

    AU - Dinis, Joana

    AU - Silva, Vânia

    AU - Gromicho, Marta

    AU - Martins, Célia

    AU - Laires, António

    AU - Tavares, P

    AU - Rendeiro, Paula

    AU - Torres, Fátima

    AU - Rueff, J.

    AU - Rodrigues, AS

    N1 - WOS:000308213400013

    PY - 2012

    Y1 - 2012

    N2 - Abstract Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.

    AB - Abstract Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.

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    KW - MBD4

    KW - MED1

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    KW - Chronic myeloid leukemia

    KW - oxidative damage

    KW - INTEGRITY

    KW - GLYCOSYLASE

    KW - genotoxicity

    KW - BASE EXCISION-REPAIR

    KW - resistance to imatinib

    KW - CHRONIC MYELOGENOUS LEUKEMIA

    KW - MECHANISMS

    U2 - 10.3109/10428194.2012.681654

    DO - 10.3109/10428194.2012.681654

    M3 - Article

    VL - 53

    SP - 2004

    EP - 2014

    JO - Leukemia & Lymphoma

    JF - Leukemia & Lymphoma

    SN - 1042-8194

    IS - 10

    ER -