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.
Blood
2010 Dec 09;11624:5298-305. doi: 10.1182/blood-2010-03-272591.
Show Gene links
Show Anatomy links
Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: implications for genomic instability and therapy.
Fan J, Li L, Small D, Rassool F.
???displayArticle.abstract???
The internal tandem duplication (ITD) mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor found in acute myeloid leukemia patients are associated with poor prognosis. Although DNA double-strand breaks (DSBs) are mainly repaired by the DNA-PK-dependent nonhomologous end-joining (NHEJ) pathway in normal mammalian cells, an alternative and less well-defined NHEJ pathway, characterized by microhomology at the repair junctions, play a role in the generation of deletions and translocations leading to cancer progression. Here we report that in FLT3/ITD-expressing cell lines and bone marrow mononuclear cells from FLT3/ITD knock-in mice, end-joining of DSBs occurs at microhomologous sequences resulting in a high frequency of DNA deletions. Strikingly, levels of Ku proteins, key components of the main NHEJ pathway, are decreased in FLT3/ITD(+) cell lines and murine FLT3/ITD bone marrow mononuclear cells. Concomitantly, levels of DNA ligase IIIα, a component of ALT NHEJ, are increased in FLT3/ITD-expressing cells. Cells treated with a FLT3 inhibitor demonstrate decreased DNA ligase IIIα and a reduction in DNA deletions, suggesting that FLT3 signaling regulates the pathways by which DSBs are repaired. Thus, therapy to inhibit FLT3/ITD signaling and/or DNA ligase IIIα may lead to repair that reduces repair errors and genomic instability.
Andrews,
Kinetic analysis of the Ku-DNA binding activity reveals a redox-dependent alteration in protein structure that stimulates dissociation of the Ku-DNA complex.
2006, Pubmed
Andrews,
Kinetic analysis of the Ku-DNA binding activity reveals a redox-dependent alteration in protein structure that stimulates dissociation of the Ku-DNA complex.
2006,
Pubmed Bao,
Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations.
2006,
Pubmed Bogue,
V(D)J recombination in Ku86-deficient mice: distinct effects on coding, signal, and hybrid joint formation.
1997,
Pubmed Boldogh,
Reduced DNA double strand breaks in chlorambucil resistant cells are related to high DNA-PKcs activity and low oxidative stress.
2003,
Pubmed Chen,
Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses.
2005,
Pubmed Chen,
Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair.
2008,
Pubmed Corneo,
Rag mutations reveal robust alternative end joining.
2007,
Pubmed Difilippantonio,
DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation.
2000,
Pubmed Falzon,
EBP-80, a transcription factor closely resembling the human autoantigen Ku, recognizes single- to double-strand transitions in DNA.
1993,
Pubmed Fan,
XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells.
2007,
Pubmed Fenaux,
Myelodysplastic syndromes: From pathogenesis and prognosis to treatment.
2004,
Pubmed 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 Gilliland,
Role of FLT3 in leukemia.
2002,
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 Hu,
ATM is down-regulated by N-Myc-regulated microRNA-421.
2010,
Pubmed Jankovic,
Antigen receptor diversification and chromosome translocations.
2007,
Pubmed John,
Targeted therapies in myeloid leukemia.
2004,
Pubmed Klassen,
Homologous recombination and the yKu70/80 complex exert opposite roles in resistance against the killer toxin from Pichia acaciae.
2007,
Pubmed Knapper,
A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy.
2006,
Pubmed Levis,
Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors.
2006,
Pubmed Levis,
In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects.
2004,
Pubmed Levis,
A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo.
2002,
Pubmed Li,
Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model.
2008,
Pubmed Lord,
Targeted therapy for cancer using PARP inhibitors.
2008,
Pubmed Markovic,
FLT-3: a new focus in the understanding of acute leukemia.
2005,
Pubmed Mimori,
Mechanism of interaction between Ku protein and DNA.
1986,
Pubmed Nakao,
Internal tandem duplication of the flt3 gene found in acute myeloid leukemia.
1996,
Pubmed Nussenzweig,
A backup DNA repair pathway moves to the forefront.
2007,
Pubmed Pratz,
A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response.
2009,
Pubmed Riballo,
A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci.
2004,
Pubmed Roth,
Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction.
1986,
Pubmed Roth,
Mechanisms of nonhomologous recombination in mammalian cells.
1985,
Pubmed Sallmyr,
Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML.
2008,
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 Seedhouse,
DNA repair contributes to the drug-resistant phenotype of primary acute myeloid leukaemia cells with FLT3 internal tandem duplications and is reversed by the FLT3 inhibitor PKC412.
2006,
Pubmed Smith,
Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia.
2004,
Pubmed Stirewalt,
FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia.
2001,
Pubmed Stirewalt,
The role of FLT3 in haematopoietic malignancies.
2003,
Pubmed Yan,
IgH class switching and translocations use a robust non-classical end-joining pathway.
2007,
Pubmed Zhu,
Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations.
2002,
Pubmed
