title: Increased c-Myc activity and DNA damage in hematopoietic progenitors precede myeloproliferative disease in Spa-1-deficiency.
abstract: Mice deficient for Spa-1 encoding Rap GTPase-activating protein develop myeloproliferative disorder (MPD) of late onset with frequent blast crises. The mechanisms for MPD development as well as the reasons for long latency, however, remain elusive. We demonstrate here that preleukemic, disease-free Spa-1(-/-) mice show reduced steady-state hematopoiesis and attenuated resistance to whole body γ-ray irradiation, which are attributable to the sustained p53 response in hematopoietic progenitor cells (HPCs). Preleukemic Spa-1(-/-) HPCs show c-Myc overexpression with increased p19Arf as well as enhanced γH2AX expression with activation of Atm/Chk pathway. We also show that deregulated Rap signaling in the absence of Spa-1 enhances post-transcriptional c-Myc stability and induces DNA damage in a p38MAPK-dependent manner, leading to p53 activation. Genetic studies indicate that the introduction of p53(+/-) and p53(-/-) mutations in Spa-1(-/-) mice results in the acceleration of typical MPD and rapid development of blastic leukemia, respectively. These results suggest that increased c-Myc expression and DNA damage in HPCs precede MPD development in Spa-1(-/-) mice, and the resulting p53 response functions as a barrier for the onset of MPD and blast crises progression.
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Tamura
authors.forename: Miho
authors.initials: M
authors.lastname: Sekai
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hamazaki
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D004249:DNA Damage; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000502:physiology*; D005720:Gamma Rays; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014916:Whole-Body Irradiation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; C489428:Myc protein, mouse; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C091108:Sipa1 protein, mouse; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins