AKT/FOXOシグナリングは,骨髄性白血病における可逆的分化ブロックを強制する

Stephen M Sykes¹, Steven W Lane, Lars Bullinger

¹Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.

Cell

|September 3, 2011

まとめ

FOXOタンパク質は,他のがんとは対照的に,急性骨髄性白血病 (AML) に有効です. FOXOまたは関連する経路を阻害すると,骨髄膜の成熟とAML細胞死が促進され,新しい治療標的が提供されます.

科学分野:

腫瘍学腫瘍学
分子生物学は分子生物学である.
血液学ヘマトロジ

背景:

AKTシグナリングは悪性腫瘍では頻繁に変化し,典型的にはFOXO腫瘍抑制剤を抑制することによって変化します.
AKT/FOXOシグナリングの対照的な役割は,急性骨髄性白血病 (AML) で観察され,FOXOが患者の重要なサブセットで活発である.

研究の目的:

急性骨髄性白血病 (AML) の分化阻害を維持するAKT/FOXO信号伝達の役割を調査する.
AMLの基礎となる分子機構を理解することによって,潜在的な治療標的を特定する.
AMLにおけるFOXOとJNK/c-JUNのシグナリングの相互作用を探求する.

主な方法:

AML患者のサンプルとMLL-AF9誘発のAMLのマウスモデルにおけるFOXO活性分析.
白血病細胞におけるAktとFoxO1/3/4の遺伝子操作.
白血病細胞の成長,白血病を誘発する細胞 (LIC) の機能,骨髄膜の成熟,および動物の生存の評価.
FOXOの活性化とJNK/c-JUNのシグナリングの相関分析.

主要な成果:

FOXOタンパク質は,遺伝子サブタイプに関係なく,AML患者のサンプルの約40%で活性化しています.
Aktの活性化またはFoxO1/3/4の削除は,マウスモデルにおける白血病細胞の成長を減少させた.
FoxO1/3/4を併用して消去すると,LICの機能が著しく低下し,生存率が向上しました.
FOXOの阻害により,骨髄膜の成熟とAML細胞死亡が誘発された.
FOXOの活性化はJNK/c-JUNのシグナル伝達と逆に相関し,耐性細胞はJNKの抑制に反応した.

結論:

アクティブFOXOシグナリングは,AMLにおける差別化ブロックを維持する上で重要な役割を果たします.
FOXOまたはJNK/c-JUNのシグナリングをターゲットにすることで,このブロックを克服し,AML細胞死と改善された結果につながります.
これらの発見は,AKT/FOXOとJNK/c-JUN経路を標的としたAMLの新しい治療戦略を明らかにしています.

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