title: ATM-dependent DNA damage-response pathway as a determinant in chronic myelogenous leukemia.
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.
authors.affiliation: Tokyo Medical and Dental University, Department of the Pediatrics and Developmental Biology, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. m.takagi.ped@tmd.ac.jp
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Masaki
authors.initials: M
authors.lastname: Sato
authors.forename: Jinhua
authors.initials: J
authors.lastname: Piao
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Isoda
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001752:Blast Crisis / Q000235:genetics* / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D016044:Fusion Proteins, bcr-abl; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases