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Blood
2010 Dec 09;11624:5298-305. doi: 10.1182/blood-2010-03-272591.
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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
.
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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,
A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo.
2002,
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,
Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors.
2006,
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,
Mechanisms of nonhomologous recombination in mammalian cells.
1985,
Pubmed
Roth,
Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction.
1986,
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,
The role of FLT3 in haematopoietic malignancies.
2003,
Pubmed
Stirewalt,
FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia.
2001,
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