| RRC ID |
44450
|
| Author |
Takagi M, Sato M, Piao J, Miyamoto S, Isoda T, Kitagawa M, Honda H, Mizutani S.
|
| Title |
ATM-dependent DNA damage-response pathway as a determinant in chronic myelogenous leukemia.
|
| Journal |
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.
|
| Volume |
12(7)
|
| Pages |
500-7
|
| Published |
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
|
| Times Cited |
14
|
|
WOS Category
|
TOXICOLOGY
GENETICS & HEREDITY
|
| Resource |
| Human and Animal Cells |
Ba/F3(RCB0805) |
