{"created":"2023-06-19T11:39:47.705941+00:00","id":7974,"links":{},"metadata":{"_buckets":{"deposit":"dec330dc-2cd0-4628-8859-5956a8d3499a"},"_deposit":{"created_by":15,"id":"7974","owners":[15],"pid":{"revision_id":0,"type":"depid","value":"7974"},"status":"published"},"_oai":{"id":"oai:mie-u.repo.nii.ac.jp:00007974","sets":["334:627:1692670222110"]},"author_link":["19337","19338","19339"],"item_8_biblio_info_6":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2008-05-01","bibliographicIssueDateType":"Issued"}}]},"item_8_description_14":{"attribute_name":"フォーマット","attribute_value_mlt":[{"subitem_description":"application/pdf","subitem_description_type":"Other"}]},"item_8_description_4":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"近年、ヒト染色体11q23から、ハエの形態形成遺伝子TrithoraxのホモログであるMLL(Mixed Lineage Leukemia)遺伝子が単離された。MLLは染色体相互転座により種々の遺伝子とキメラを形成し、白血病を引き起こす。特に乳児白血病の場合は、ほとんどがMLLキメラ遺伝子が原因であり、その発病は子宮内であることが示唆されている。我々はレトロウイルス発現系とマウス骨髄移植の系を用いて、MLL キメラ遺伝子による乳児白血病発症に近い状態をマウスにおいて再現することに成功した。即ち、MLLキメラ遺伝子単独発現では骨髄増殖性疾患(MPD)を発症するのみであるが、付加的遺伝子異常として、受容体型チロシンキナーゼであるFLT3の恒常的活性型変異体ITD(internal tandem duplication)を共発現させると、急性骨髄性白血病(AML)が発症した。FLT3 ITD変異体のみの発現では無症状もしくはMPDを発症するのみでAMLは起きなかった。これはMLLキメラ遺伝子による乳児白血病発症には少なくとも2 種類の遺伝子変異が必要であることを意味する。さらにMLL-SELPT6というキメラ遺伝子を用いたin vitro実験により、MLL-SEPT6蛋白はホモ多量体形成により機能を発揮し、HoxA7、HoxA9などの下流の遺伝子発現を上昇させることが明らかになった。\n次に、FLT3ITD変異体のかわりにFLT3TKD(tyrosine kinase domain)変異体を用いて同様の実験を行うと、単独発現の場合はTKDの方がITDよりも活性が弱かったにもかかわらず、MLL-SEPT6と共発現させると、より強い協調作用を示し、同じ潜伏期でAMLを発症させた。下流のシグナルを解析すると、ITDではSTAT5経路、TKDではRas- Raf-MAPK経路のシグナルへの依存性が強かった。すなわち、MLLキメラ蛋白はSTAT5よりもRas-Raf-MAPK経路との協調作用が強いことが示唆された。実際、MLL-SEPT6を発現するIL-3依存性細胞株において、恒常的活性型STAT5の強発現ではIL-3非依存性増殖を示さなかったのに対し、活性型Rafの強発現ではIL-3非依存性に増殖した。さらに、MLLキメラ蛋白の下流遺伝子の一つであるHoxA9と活性型Rasの共発現でも、AMLに近い病態が誘導された。したがって、MLLキメラ蛋白による白血病発症の分子機構はHoxA9による自己複製能とRas-Raf- MAPK経路による細胞増殖活性の両者の協調作用に集約される可能性が示された。","subitem_description_type":"Abstract"}]},"item_8_description_5":{"attribute_name":"内容記述","attribute_value_mlt":[{"subitem_description":"平成18〜19年度科学研究費補助金(基盤研究(B))研究成果報告書","subitem_description_type":"Other"},{"subitem_description":"津","subitem_description_type":"Other"}]},"item_8_description_62":{"attribute_name":"目次","attribute_value_mlt":[{"subitem_description":"MLL関連白血病の分子病態 (<特集>白血病の分子病態 : 最近の進歩)","subitem_description_type":"Other"},{"subitem_description":"造血器腫瘍マウスモデル(<特集>シグナル伝達系の変異から : Interface on cancer therapy : Basic science)","subitem_description_type":"Other"}]},"item_8_description_64":{"attribute_name":"科研費番号","attribute_value_mlt":[{"subitem_description":"18390278","subitem_description_type":"Other"}]},"item_8_publisher_30":{"attribute_name":"出版者","attribute_value_mlt":[{"subitem_publisher":"野阪哲哉"}]},"item_8_relation_46":{"attribute_name":"部分を持つ","attribute_value_mlt":[{"subitem_relation_type":"hasPart","subitem_relation_type_id":{"subitem_relation_type_id_text":"http://hdl.handle.net/10076/10420","subitem_relation_type_select":"URI"}},{"subitem_relation_type":"hasPart","subitem_relation_type_id":{"subitem_relation_type_id_text":"http://hdl.handle.net/10076/9313","subitem_relation_type_select":"URI"}}]},"item_8_subject_16":{"attribute_name":"日本十進分類法","attribute_value_mlt":[{"subitem_subject":"490","subitem_subject_scheme":"NDC"}]},"item_8_text_65":{"attribute_name":"資源タイプ（三重大）","attribute_value_mlt":[{"subitem_text_value":"Kaken / 科研費報告書"}]},"item_8_version_type_15":{"attribute_name":"著者版フラグ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_970fb48d4fbd8a85","subitem_version_type":"VoR"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"野阪, 哲哉","creatorNameLang":"ja"}],"nameIdentifiers":[{"nameIdentifier":"19337","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"北村, 俊雄","creatorNameLang":"ja"}],"nameIdentifiers":[{"nameIdentifier":"19338","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"小埜, 良一","creatorNameLang":"ja"}],"nameIdentifiers":[{"nameIdentifier":"19339","nameIdentifierScheme":"WEKO"}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2017-02-18"}],"displaytype":"detail","filename":"30K8008.pdf","filesize":[{"value":"564.6 kB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"30K8008.pdf","url":"https://mie-u.repo.nii.ac.jp/record/7974/files/30K8008.pdf"},"version_id":"e12bbf96-0e1a-459a-ab71-ce2f50865178"}]},"item_keyword":{"attribute_name":"キーワード","attribute_value_mlt":[{"subitem_subject":"MLL","subitem_subject_scheme":"Other"},{"subitem_subject":"11q23染色体転座","subitem_subject_scheme":"Other"},{"subitem_subject":"乳児白血病","subitem_subject_scheme":"Other"},{"subitem_subject":"Ras","subitem_subject_scheme":"Other"},{"subitem_subject":"Raf","subitem_subject_scheme":"Other"},{"subitem_subject":"MAPK","subitem_subject_scheme":"Other"},{"subitem_subject":"Hox","subitem_subject_scheme":"Other"},{"subitem_subject":"STAT5","subitem_subject_scheme":"Other"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"research report","resourceuri":"http://purl.org/coar/resource_type/c_18ws"}]},"item_title":"白血病幹細胞の自己複製能を担う分子機構と白血病発症に至る分子機序の解明","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"白血病幹細胞の自己複製能を担う分子機構と白血病発症に至る分子機序の解明","subitem_title_language":"ja"}]},"item_type_id":"8","owner":"15","path":["1692670222110"],"pubdate":{"attribute_name":"PubDate","attribute_value":"2009-01-09"},"publish_date":"2009-01-09","publish_status":"0","recid":"7974","relation_version_is_last":true,"title":["白血病幹細胞の自己複製能を担う分子機構と白血病発症に至る分子機序の解明"],"weko_creator_id":"15","weko_shared_id":-1},"updated":"2023-08-29T04:36:22.283873+00:00"}