JP2010503420A - 慢性リンパ球性白血病におけるmiR−29およびmiR−181によって制御されるTCL1発現 - Google Patents
慢性リンパ球性白血病におけるmiR−29およびmiR−181によって制御されるTCL1発現 Download PDFInfo
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- JP2010503420A JP2010503420A JP2009529212A JP2009529212A JP2010503420A JP 2010503420 A JP2010503420 A JP 2010503420A JP 2009529212 A JP2009529212 A JP 2009529212A JP 2009529212 A JP2009529212 A JP 2009529212A JP 2010503420 A JP2010503420 A JP 2010503420A
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Abstract
【選択図】 図1
Description
該当無し(N/A)。
政府援助
本発明はNIH Grant/Contact Number PO1 CA81534から得た補助金によって、すべてまたは一部が援助された。政府は本発明にある程度の権利を有する。
一定のmiR遺伝子産物のノーザンブロットハイブリダイゼーションに適切なプローブは一定のmiRの核酸配列から生産することができる。標識されたDNAおよびRNAプローブの作製方法、および標的核酸配列に対するそのハイブリダイゼーションの条件は、Molecular Cloning:A Laboratory Manual,J.Sambrook et al.,編,2版,Cold Spring Harbor Laboratory Press,1989,10および11章に記載され、その開示は参照として本明細書に援用される。
DNA‐コンストラクト、トランスフェクション、ウェスタンブロッティングおよびルシフェラーゼアッセイ。
結果と考察
Tcl1の高発現は侵襲性B−CLL表現型に相関する
B−CLL試料におけるTCL1およびマイクロRNA発現を評価するために、3群のB−CLL:23の低侵襲性B−CLL試料、25の侵襲性B−CLL試料および32の11q欠失を示す侵襲性B−CLL試料が選択された。試料の詳細な説明は図4a〜4dに示す。
miR−29およびmiR標的Tcl1発現
どのmiRNAがTCL1を標的にするかを確定するために、Bielefeld University Bioinformatics Server and miRBaseデータベースにより提供されたRNAハイブリッドソフトウェア13が使用された。TCL1を標的にするmiR−候補の中で、miR−29bおよびmiR−181b(図1c、相同性がより低いいくつかの他の部位は示さない)は11qが欠失した侵襲性B−CLLにおいてもダウンレギュレーションされていることが見いだされた(図3−表1)。
参考文献
先に論じた参考文献および以下の参考文献は、それらが代表的な手順、またはその他の詳細の捕捉を提供する程度に、特に参照として本明細書に援用される。
Claims (30)
- 対象由来の試験試料における少なくとも1つのmiR遺伝子産物のレベルを測定することを含む、該対象が慢性リンパ球性白血病(B−CLL)に罹患しているか、またはそれを発症するリスクがあるかを診断する方法であって、試験試料のmiR遺伝子産物のレベルを対照試料の対応するmiR遺伝子産物のレベルに比較した変化が、対象がB−CLLに罹患しているか、またはそれを発症するリスクがあるかのいずれかであることを表す、方法。
- 少なくとも1つのmiR遺伝子産物がmiR−29またはmiR−181である、請求項1に記載の方法。
- 少なくとも1つのmiR遺伝子産物がmiR−29bである、請求項1に記載の方法。
- 少なくとも1つのmiR遺伝子産物がmiR−181bである、請求項1に記載の方法。
- 少なくとも1つのmiR遺伝子産物のレベルがノーザンブロット解析を使用して測定される、請求項1に記載の方法。
- 試験試料における少なくとも1つのmiR遺伝子産物のレベルが、対照試料における対応するmiR遺伝子産物のレベルより少ない、請求項1に記載の方法。
- 試験試料における少なくとも1つのmiR遺伝子産物のレベルが、対照試料における対応するmiR遺伝子産物のレベルより多い、請求項1に記載の方法。
- 対象に由来するB−CLL試料における少なくとも1つのmiR遺伝子産物のレベルを測定することを含む、対象における1つ以上の予後マーカーに関連したB−CLLを診断する方法であって、試験試料のmiR遺伝子産物のレベルを対照試料の対応するmiR遺伝子産物のレベルに比較した変化が、対象がB−CLLに罹患しているか、またはそれを発症するリスクがあるかのいずれかであることを表す、方法。
- 対象がB−CLLに罹患しているか、またはそれを発症するリスクがあるかを診断する方法であって、以下:
(1)対象から得られた試験試料からRNAを逆転写して、1組の標的オリゴデオキシヌクレオチドを提供すること;
(2)miRNA‐特有プローブオリゴヌクレオチドを含むマイクロアレイに標的オリゴデオキシヌクレオチドをハイブリダイズし、試験試料のハイブリダイゼーションプロファイルを提供すること;および
(3)試験試料ハイブリダイゼーションプロファイルと対照試料から生み出されたハイブリダイゼーションプロファイルを比較することを含み、少なくとも1つのmiRNAにおけるシグナルの変化が、対象がB−CLLに罹患しているか、またはそれを発症するリスクがあるかのいずれかであることを表す、方法。 - 少なくとも1つのmiRNAのシグナルが、対照試料から生み出されたシグナルに比較してダウンレギュレーションされている、請求項9に記載の方法。
- 少なくとも1つのmiRNAのシグナルが、対照試料から生み出されたシグナルに比較してアップレギュレーションされている、請求項9に記載の方法。
- マイクロアレイが、miR−29またはmiR−181およびその組み合わせからなる群から選択される1つ以上のmiRNAのmiRNA‐特有プローブオリゴヌクレオチドを含む、請求項9に記載の方法。
- 対象が、対象における1つ以上の有害な予後マーカーに関連するB−CLLに罹患しているか、またはそれを発症するリスクがあるかを診断する方法であって、以下:
(1)対象から得られた試験試料からRNAを逆転写して、1組の標的オリゴデオキシヌクレオチドを提供すること;
(2)miRNA‐特有プローブオリゴヌクレオチドを含むマイクロアレイに標的オリゴデオキシヌクレオチドをハイブリダイズし、試験試料のハイブリダイゼーションプロファイルを提供すること;および
(3)試験試料ハイブリダイゼーションプロファイルと対照試料から生み出されたハイブリダイゼーションプロファイルを比較することを含み、シグナルにおける変化が対象が癌に罹患しているか、またはそれを発症するリスクがあるかのいずれかであることを表す、方法。 - マイクロアレイが、miR−29またはmiR−181およびその組み合わせからなる群から選択されるmiRNAの少なくとも1つのmiRNA‐特有プローブオリゴヌクレオチドを含む、請求項13に記載の方法。
- 少なくとも1つのmiR遺伝子産物が、対照細胞に比較して対象の癌細胞においてダウンレギュレーションされているか、またはアップレギュレーションされているB−CLLに罹患している対象のB−CLLを治療する方法であって、以下:
(1)少なくとも1つのmiR遺伝子産物が癌細胞においてダウンレギュレーションされている場合、有効量の少なくとも1つの単離されたmiR遺伝子産物を対象に投与して、対象における癌細胞の増殖を阻害すること;または
(2)少なくとも1つのmiR遺伝子産物が癌細胞においてアップレギュレーションされている場合、少なくとも1つのmiR遺伝子産物の発現を阻害するための有効量の少なくとも1つの化合物を対象に投与して、対象における癌細胞の増殖を阻害することを含む、方法。 - ステップ(1)の少なくとも1つの単離されたmiR遺伝子産物がmiR−29、miR−181、およびその組み合わせから選択される、請求項15に記載の方法。
- ステップ(2)の少なくとも1つのmiR遺伝子産物がmiR−29、miR−181、およびその組み合わせからなる群から選択される、請求項15に記載の方法。
- 対象においてB−CLLを治療する方法であって、以下:
(1)B−CLLにおける少なくとも1つのmiR遺伝子産物の量を対照細胞に比較して確定すること;および
(2)i)癌細胞に発現されたmiR遺伝子産物の量が、対照細胞において発現されたmiR遺伝子産物の量より少ない場合、有効量の少なくとも1つの単離されたmiR遺伝子産物を対象に投与すること;または
ii)癌細胞に発現されたmiR遺伝子産物の量が、対照細胞において発現されたmiR遺伝子産物の量より多い場合、少なくとも1つのmiR遺伝子産物の発現を阻害する有効量の少なくとも1つの化合物を対象に投与して、対象における癌細胞の増殖を阻害することによってB−CLL細胞に発現されるmiR遺伝子産物の量を変化させることを含む、方法。 - ステップ(1)の少なくとも1つの単離されたmiR遺伝子産物がmiR−29、miR−181、およびその組み合わせからなる群から選択される、請求項18に記載の方法。
- ステップ(2)の少なくとも1つのmiR遺伝子産物がmiR−29、miR−181、およびその組み合わせからなる群から選択される、請求項18に記載の方法。
- 少なくとも1つの単離されたmiR遺伝子産物および薬剤的に受容できるキャリアを含む、B−CLLを治療するための医薬組成物。
- 少なくとも1つの単離されたmiR遺伝子産物が、適切な対照細胞に比較してB−CLL細胞においてダウンレギュレーションされているmiR遺伝子産物に対応する、請求項21に記載の医薬組成物。
- 単離されたmiR遺伝子産物がmiR−29、miR−181、およびその組み合わせからなる群から選択される、請求項22に記載の医薬組成物。
- 少なくとも1つのmiR発現阻害化合物および薬剤的に受容できるキャリアを含む、B−CLLを治療するための医薬組成物。
- 少なくとも1つのmiR発現阻害化合物が、適切な対照細胞に比較してB−CLL細胞においてアップレギュレーションされているmiR遺伝子産物に特有である、請求項24に記載の医薬組成物。
- 少なくとも1つのmiR発現阻害化合物がmiR−29、miR−181、およびその組み合わせからなる群から選択されるmiR遺伝子産物に特有である、請求項25に記載の医薬組成物。
- 細胞に試験薬剤を提供すること、およびB−CLL細胞における減少した発現レベルに関連した少なくとも1つのmiR遺伝子産物のレベルを測定することを含む、抗‐B−CLL剤を確認する方法であって、適切な対照細胞に比較した該細胞におけるmiR遺伝子産物のレベルの増加が、試験薬剤が抗‐B−CLL剤であることを表す、方法。
- miR遺伝子産物がmiR−29、miR−181、およびその組み合わせからなる群から選択される、請求項27に記載の方法。
- 細胞に試験薬剤を提供すること、およびB−CLL細胞における増加した発現レベルに関連した少なくとも1つのmiR遺伝子産物のレベルを測定することを含む、抗‐B−CLL剤を確認する方法であって、適切な対照細胞に比較した該細胞におけるmiR遺伝子産物のレベルの減少が、試験薬剤が抗‐B−CLL剤であることを表す、方法。
- miR遺伝子産物がmiR−29、miR−181、およびその組み合わせからなる群から選択される、請求項29に記載の方法。
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WO2005118806A2 (en) * | 2004-05-28 | 2005-12-15 | Ambion, Inc. | METHODS AND COMPOSITIONS INVOLVING MicroRNA |
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JPN6012054286; N. Engl. J. Med. Vol.353, 2005, p.1793-1801 * |
JPN6012054289; PNAS Vol.101, 2004, p.2999-3004 * |
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CA2663027A1 (en) | 2008-08-14 |
EP2061907A2 (en) | 2009-05-27 |
EP2061907A4 (en) | 2010-08-04 |
AU2007346101B2 (en) | 2013-08-15 |
JP5426383B2 (ja) | 2014-02-26 |
JP2014113146A (ja) | 2014-06-26 |
AU2007346101A1 (en) | 2008-08-14 |
WO2008097277A3 (en) | 2008-10-09 |
CN101535505A (zh) | 2009-09-16 |
US8071292B2 (en) | 2011-12-06 |
EP2061907B1 (en) | 2011-11-23 |
ES2374446T3 (es) | 2012-02-16 |
ATE534752T1 (de) | 2011-12-15 |
US20100004322A1 (en) | 2010-01-07 |
WO2008097277A2 (en) | 2008-08-14 |
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