Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias.
Tobin LA, Robert C, Rapoport AP, Gojo I, Baer MR, Tomkinson AE, Rassool FV.
???displayArticle.abstract???
Resistance to imatinib (IM) and other tyrosine kinase inhibitors (TKI)s is an increasing problem in leukemias caused by expression of BCR-ABL1. As chronic myeloid leukemia (CML) cell lines expressing BCR-ABL1 utilize an alternative non-homologous end-joining pathway (ALT NHEJ) to repair DNA double-strand breaks (DSB)s, we asked whether this repair pathway is a novel therapeutic target in TKI-resistant disease. Notably, the steady state levels of two ALT NHEJ proteins, poly-(ADP-ribose) polymerase 1 (PARP1) and DNA ligase IIIα, were increased in the BCR-ABL1-positive CML cell line K562 and, to a greater extent, in its imatinib-resistant (IMR) derivative. Incubation of these cell lines with a combination of DNA ligase and PARP inhibitors inhibited ALT NHEJ and selectively decreased survival with the effect being greater in the IMR derivative. Similar results were obtained with TKI-resistant derivatives of two hematopoietic cell lines that had been engineered to stably express BCR-ABL1. Together our results show that the sensitivity of cell lines expressing BCR-ABL1 to the combination of DNA ligase and PARP inhibitors correlates with the steady state levels of PARP1 and DNA ligase IIIα, and ALT NHEJ activity. Importantly, analysis of clinical samples from CML patients confirmed that the expression levels of PARP1 and DNA ligase IIIα correlated with the sensitivity to the DNA repair inhibitor combination. Thus, the expression levels of PARP1 and DNA ligase IIIα serve as biomarkers to identify a subgroup of CML patients who may be candidates for therapies that target the ALT NHEJ pathway when treatment with TKIs has failed.
Audebert,
Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway.
2006, Pubmed
Audebert,
Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway.
2006,
Pubmed Audebert,
Effect of double-strand break DNA sequence on the PARP-1 NHEJ pathway.
2008,
Pubmed Audebert,
Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining.
2004,
Pubmed Ayene,
Mutation in the glucose-6-phosphate dehydrogenase gene leads to inactivation of Ku DNA end binding during oxidative stress.
2002,
Pubmed Brady,
Increased error-prone NHEJ activity in myeloid leukemias is associated with DNA damage at sites that recruit key nonhomologous end-joining proteins.
2003,
Pubmed Branford,
High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance.
2002,
Pubmed Branford,
Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis.
2003,
Pubmed Bryant,
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
2005,
Pubmed Chen,
Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair.
2008,
Pubmed de Smith,
Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases.
2007,
Pubmed Falzon,
EBP-80, a transcription factor closely resembling the human autoantigen Ku, recognizes single- to double-strand transitions in DNA.
1993,
Pubmed Fan,
Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: implications for genomic instability and therapy.
2010,
Pubmed
,
Xenbase Fattah,
Ku regulates the non-homologous end joining pathway choice of DNA double-strand break repair in human somatic cells.
2010,
Pubmed Foster,
Functional interplay of the Mre11 nuclease and Ku in the response to replication-associated DNA damage.
2011,
Pubmed Gao,
DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair.
2011,
Pubmed
,
Xenbase Gaymes,
Myeloid leukemias have increased activity of the nonhomologous end-joining pathway and concomitant DNA misrepair that is dependent on the Ku70/86 heterodimer.
2002,
Pubmed Gorre,
Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.
2001,
Pubmed Gottlieb,
The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen.
1993,
Pubmed Grawunder,
Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells.
1997,
Pubmed Hehlmann,
Treatment of chronic myeloid leukemia when imatinib fails.
2011,
Pubmed Jabbour,
Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia.
2011,
Pubmed Krishnakumar,
Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes.
2008,
Pubmed le Coutre,
Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification.
2000,
Pubmed Lee-Theilen,
CtIP promotes microhomology-mediated alternative end joining during class-switch recombination.
2011,
Pubmed Löbrich,
DNA double-strand break measurement in mammalian cells by pulsed-field gel electrophoresis: an approach using restriction enzymes and gene probing.
1994,
Pubmed Lord,
Targeted therapy for cancer using PARP inhibitors.
2008,
Pubmed Ma,
A biochemically defined system for mammalian nonhomologous DNA end joining.
2004,
Pubmed Mahon,
Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance.
2000,
Pubmed Majsterek,
Does the bcr/abl-mediated increase in the efficacy of DNA repair play a role in the drug resistance of cancer cells?
2002,
Pubmed Mimori,
Mechanism of interaction between Ku protein and DNA.
1986,
Pubmed Nowicki,
BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks.
2004,
Pubmed Nussenzweig,
A backup DNA repair pathway moves to the forefront.
2007,
Pubmed Ohmine,
Analysis of gene expression profiles in an imatinib-resistant cell line, KCL22/SR.
2003,
Pubmed Rowley,
Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining.
1973,
Pubmed RUDKIN,
DNA CONTENTS OF CHROMOSOME PH1 AND CHROMOSOME 21 IN HUMAN CHRONIC GRANULOCYTIC LEUKEMIA.
1964,
Pubmed Sallmyr,
Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks.
2008,
Pubmed
,
Xenbase Sartori,
Human CtIP promotes DNA end resection.
2007,
Pubmed Sattler,
The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells.
2000,
Pubmed Savage,
Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period.
1997,
Pubmed Shah,
Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia.
2002,
Pubmed Simsek,
Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair.
2011,
Pubmed
,
Xenbase Skorski,
BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability.
2002,
Pubmed Slupianek,
Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis.
2002,
Pubmed Soverini,
ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.
2005,
Pubmed Spiers,
Clinical manifestations of chronic granulocytic leukemia.
1995,
Pubmed Tobin,
Targeting abnormal DNA repair in therapy-resistant breast cancers.
2012,
Pubmed Tsai,
Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends.
2007,
Pubmed von Bubnoff,
BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study.
2002,
Pubmed Wang,
DNA ligase III as a candidate component of backup pathways of nonhomologous end joining.
2005,
Pubmed Wang,
PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways.
2006,
Pubmed Weisberg,
Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines.
2000,
Pubmed Zhang,
An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway.
2011,
Pubmed Zhong,
Identification and validation of human DNA ligase inhibitors using computer-aided drug design.
2008,
Pubmed
