神経芽細胞腫におけるALKキナーゼ受容体の体内および生殖線活性化変異
Isabelle Janoueix-Lerosey1, Delphine Lequin, Laurence Brugières
1Institut Curie, Centre de Recherche, and Inserm, U830, 26 rue d'Ulm, Paris F-75248, France.
Nature
|October 17, 2008
まとめ
アナプラスティックリンパ腫キナーゼ (ALK) 遺伝子の増幅と変異は,一般的な小児がんであるニューロブラストーマの主要な要因です. ALKをターゲットにすることは,このしばしば致命的な病気に対する有望な治療戦略です.
科学分野:
- 腫瘍学 腫瘍学
- 遺伝学 遺伝学とは
- 分子生物学は分子生物学である.
背景:
- 神経芽細胞腫は,外周交感性神経系から発生する子供期の固体腫瘍です.
- しばしば散発的であるが,家族的な症例と先天性不形成との関連は,遺伝的根拠を示唆する.
研究 の 目的:
- ニューロブラストーマの遺伝子変化を調査し,腫瘍発達の潜在的な要因に焦点を当てます.
- ニューロブラストーマ治療の新たな治療標的を特定する.
主な方法:
- ゲノム全体の比較ゲノムハイブリデーション (CGH) は,多数の神経芽細胞腫で実施されました.
- 細胞系と原発腫瘍におけるALKキナーゼドメインの直接シーケンシング.
- 遺伝子ノックダウンとタンパク質活性アッセイを含む機能研究.
主要な成果:
- アナプラスティックリンパ腫キナーゼ (ALK) 局所における複製数の再発的増加が特定されました.
- ALKキナーゼドメイン内のソマティック変異は,神経芽細胞腫のサンプルで発見されました.
- ゲルムラインALK変異は,家族性ニューロブラストーマ症例で観察され,ALKを予備性遺伝子として確立しました.
- 変異したALKタンパク質は過剰発現,高酸化,構成キナーゼ活性を示した.
- ALK阻害は,変異状態に関係なく,神経芽細胞の増殖を著しく減少させました.
結論:
- ALKはニューロブラストーマ発症における重要な腫瘍原発因子である.
- ALKは,現在治療の選択肢が限られている疾患であるニューロブラストーマの重要な治療目標です.
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