Increased c‐Myc activity and DNA damage in hematopoietic progenitors precede myeloproliferative disease in Spa‐1‐deficiency
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...
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| Veröffentlicht in: | Cancer science 2011-04, Vol.102 (4), p.784-791 |
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| creator | Tanaka, Hiroki Tamura, Akitoshi Sekai, Miho Hamazaki, Yoko Minato, Nagahiro |
| description | 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. (Cancer Sci 2011; 102: 784–791) |
| doi_str_mv | 10.1111/j.1349-7006.2011.01850.x |
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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. (Cancer Sci 2011; 102: 784–791)</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/j.1349-7006.2011.01850.x</identifier><identifier>PMID: 21205094</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Biological and medical sciences ; Blast Crisis - etiology ; Blast Crisis - metabolism ; Blast Crisis - pathology ; Blotting, Western ; DNA Damage ; Flow Cytometry ; Gamma Rays ; GTPase-Activating Proteins - physiology ; Hematologic and hematopoietic diseases ; Hematopoiesis ; Hematopoietic Stem Cells - physiology ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation - genetics ; Myeloproliferative Disorders - etiology ; Myeloproliferative Disorders - metabolism ; Myeloproliferative Disorders - pathology ; Nuclear Proteins - physiology ; p38 Mitogen-Activated Protein Kinases - genetics ; p38 Mitogen-Activated Protein Kinases - metabolism ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; rap1 GTP-Binding Proteins - genetics ; rap1 GTP-Binding Proteins - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Signal Transduction ; Survival Rate ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Whole-Body Irradiation</subject><ispartof>Cancer science, 2011-04, Vol.102 (4), p.784-791</ispartof><rights>2011 Japanese Cancer Association</rights><rights>2015 INIST-CNRS</rights><rights>2011 Japanese Cancer Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5820-66b487e667ad3de77f4f0d716a2efd614d438107c5b0f6a1407da0afd4eb5f4c3</citedby><cites>FETCH-LOGICAL-c5820-66b487e667ad3de77f4f0d716a2efd614d438107c5b0f6a1407da0afd4eb5f4c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1349-7006.2011.01850.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1349-7006.2011.01850.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,11562,27924,27925,45574,45575,46052,46476</link.rule.ids><linktorsrc>$$Uhttps://onlinelibrary.wiley.com/doi/abs/10.1111%2Fj.1349-7006.2011.01850.x$$EView_record_in_Wiley-Blackwell$$FView_record_in_$$GWiley-Blackwell</linktorsrc><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24086001$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21205094$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tanaka, Hiroki</creatorcontrib><creatorcontrib>Tamura, Akitoshi</creatorcontrib><creatorcontrib>Sekai, Miho</creatorcontrib><creatorcontrib>Hamazaki, Yoko</creatorcontrib><creatorcontrib>Minato, Nagahiro</creatorcontrib><title>Increased c‐Myc activity and DNA damage in hematopoietic progenitors precede myeloproliferative disease in Spa‐1‐deficiency</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>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. (Cancer Sci 2011; 102: 784–791)</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blast Crisis - etiology</subject><subject>Blast Crisis - metabolism</subject><subject>Blast Crisis - pathology</subject><subject>Blotting, Western</subject><subject>DNA Damage</subject><subject>Flow Cytometry</subject><subject>Gamma Rays</subject><subject>GTPase-Activating Proteins - physiology</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hematopoiesis</subject><subject>Hematopoietic Stem Cells - physiology</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mutation - genetics</subject><subject>Myeloproliferative Disorders - etiology</subject><subject>Myeloproliferative Disorders - metabolism</subject><subject>Myeloproliferative Disorders - pathology</subject><subject>Nuclear Proteins - physiology</subject><subject>p38 Mitogen-Activated Protein Kinases - genetics</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>rap1 GTP-Binding Proteins - genetics</subject><subject>rap1 GTP-Binding Proteins - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>Signal Transduction</subject><subject>Survival Rate</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><subject>Whole-Body Irradiation</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkM9u1DAQxiMEoqXwCsgXxCnpOHFs74HDaoFSqZRD4WzN2uPiVf4scRaaG30DnpEnqdNdyrWWRv6k-c18oy_LGIeCp3e6KXglFrkCkEUJnBfAdQ3FzZPs-KHx9F6rfAFVeZS9iHEDUEmxEM-zo5KXUMNCHGe3550dCCM5Zv_-_vN5sgztGH6GcWLYOfb-cskctnhNLHTsO7U49ts-0Bgs2w79NXVh7IeYNFlyxNqJmj41muBpwLSImAtxNpjnr7aYTHgqRz7YQJ2dXmbPPDaRXh3-k-zbxw9fV5_yiy9n56vlRW5rXUIu5VpoRVIqdJUjpbzw4BSXWJJ3kgsnKs1B2XoNXiIXoBwCeidoXXthq5Ps7X5vuu7HjuJo2hAtNQ121O-i0bXSXGjQidR70g59jAN5sx1Ci8NkOJg5f7Mxc8xmjtnM-Zv7_M1NGn19MNmtW3IPg_8CT8CbA4DRYuMH7GyI_zkBWgLwxL3bc79CQ9OjDzCr5dWsqjtdc6Wk</recordid><startdate>201104</startdate><enddate>201104</enddate><creator>Tanaka, Hiroki</creator><creator>Tamura, Akitoshi</creator><creator>Sekai, Miho</creator><creator>Hamazaki, Yoko</creator><creator>Minato, Nagahiro</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201104</creationdate><title>Increased c‐Myc activity and DNA damage in hematopoietic progenitors precede myeloproliferative disease in Spa‐1‐deficiency</title><author>Tanaka, Hiroki ; Tamura, Akitoshi ; Sekai, Miho ; Hamazaki, Yoko ; Minato, Nagahiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5820-66b487e667ad3de77f4f0d716a2efd614d438107c5b0f6a1407da0afd4eb5f4c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blast Crisis - etiology</topic><topic>Blast Crisis - metabolism</topic><topic>Blast Crisis - pathology</topic><topic>Blotting, Western</topic><topic>DNA Damage</topic><topic>Flow Cytometry</topic><topic>Gamma Rays</topic><topic>GTPase-Activating Proteins - physiology</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Hematopoiesis</topic><topic>Hematopoietic Stem Cells - physiology</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mutation - genetics</topic><topic>Myeloproliferative Disorders - etiology</topic><topic>Myeloproliferative Disorders - metabolism</topic><topic>Myeloproliferative Disorders - pathology</topic><topic>Nuclear Proteins - physiology</topic><topic>p38 Mitogen-Activated Protein Kinases - genetics</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>rap1 GTP-Binding Proteins - genetics</topic><topic>rap1 GTP-Binding Proteins - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>Signal Transduction</topic><topic>Survival Rate</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><topic>Whole-Body Irradiation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tanaka, Hiroki</creatorcontrib><creatorcontrib>Tamura, Akitoshi</creatorcontrib><creatorcontrib>Sekai, Miho</creatorcontrib><creatorcontrib>Hamazaki, Yoko</creatorcontrib><creatorcontrib>Minato, Nagahiro</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Tanaka, Hiroki</au><au>Tamura, Akitoshi</au><au>Sekai, Miho</au><au>Hamazaki, Yoko</au><au>Minato, Nagahiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased c‐Myc activity and DNA damage in hematopoietic progenitors precede myeloproliferative disease in Spa‐1‐deficiency</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2011-04</date><risdate>2011</risdate><volume>102</volume><issue>4</issue><spage>784</spage><epage>791</epage><pages>784-791</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><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. (Cancer Sci 2011; 102: 784–791)</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21205094</pmid><doi>10.1111/j.1349-7006.2011.01850.x</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Blast Crisis - etiology Blast Crisis - metabolism Blast Crisis - pathology Blotting, Western DNA Damage Flow Cytometry Gamma Rays GTPase-Activating Proteins - physiology Hematologic and hematopoietic diseases Hematopoiesis Hematopoietic Stem Cells - physiology Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Mutation - genetics Myeloproliferative Disorders - etiology Myeloproliferative Disorders - metabolism Myeloproliferative Disorders - pathology Nuclear Proteins - physiology p38 Mitogen-Activated Protein Kinases - genetics p38 Mitogen-Activated Protein Kinases - metabolism Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism rap1 GTP-Binding Proteins - genetics rap1 GTP-Binding Proteins - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Signal Transduction Survival Rate Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors Whole-Body Irradiation |
| title | Increased c‐Myc activity and DNA damage in hematopoietic progenitors precede myeloproliferative disease in Spa‐1‐deficiency |
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