RRC ID 44450
著者 Takagi M, Sato M, Piao J, Miyamoto S, Isoda T, Kitagawa M, Honda H, Mizutani S.
タイトル ATM-dependent DNA damage-response pathway as a determinant in chronic myelogenous leukemia.
ジャーナル DNA Repair (Amst)
Abstract Chronic myelogenous leukemia (CML) begins with an indolent chronic phase, and subsequently progresses to an accelerated or blastic phase. Although several genes are known to be involved in the progression to blastic phase, molecular mechanisms for the evolution toward blast crisis have not been fully identified. Oncogenic stimuli enforce cell proliferation, which requires DNA replication. Unscheduled DNA replication enforced by oncogenic stimuli leads to double strand breaks on DNA. We found the DNA damage-response pathway is activated in bone marrow of chronic-phase CML patients possibly due to an enforced proliferation signal by BCR-ABL expression. Since ataxia telangiectasia mutated (ATM) is a central player of the DNA damage-response pathway, we studied whether loss of this pathway accelerates blast crisis. We crossed Atm-knockout mice with BCR-ABL transgenic mice to test this hypothesis. Interestingly, the loss of one of the Atm alleles was shown to be enough for the acceleration of the blast crisis, which is supported by the finding of increased genomic instability as assayed by breakage-fusion-bridge (BFB) cycle formation. In light of these findings, the DNA damage-response pathway plays a vital role for determination of susceptibility to blast crisis in CML.
巻・号 12(7)
ページ 500-7
公開日 2013-7-1
DOI 10.1016/j.dnarep.2013.04.022
PII S1568-7864(13)00103-1
PMID 23694754
MeSH Animals Ataxia Telangiectasia Mutated Proteins Blast Crisis / genetics* Blast Crisis / metabolism Bone Marrow / metabolism Bone Marrow / pathology Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Cell Line, Tumor Cell Proliferation DNA Damage* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Fusion Proteins, bcr-abl / genetics Fusion Proteins, bcr-abl / metabolism Mice Mice, Knockout Mutation Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism* Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism*
IF 3.339
引用数 14
WOS 分野 TOXICOLOGY GENETICS & HEREDITY
リソース情報
ヒト・動物細胞 Ba/F3(RCB0805)