骨髄性白血病におけるBCAA代謝の再プログラムによる癌の進行
Ayuna Hattori1,2, Makoto Tsunoda3, Takaaki Konuma4
1Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, The University of Georgia, Athens, Georgia 30602, USA.
Nature
|May 18, 2017
まとめ
BCAT1によって調節される分岐鎖アミノ酸 (BCAA) の代謝は慢性骨髄性白血病 (CML) の進行を促します. MSI2- BCAT1経路をターゲットにすることで,骨髄性白血病の新たな治療戦略が提供されます.
科学分野:
- 腫瘍学
- 代謝経路
- 癌の生物学
背景:
- 再プログラムされた細胞代謝は癌の特徴ですが,癌の発生における直接的な役割は不明です.
- 分岐鎖アミノ酸 (BCAA) は不可欠な栄養素であり,がんにおけるその代謝失調についてはさらなる調査が必要である.
- 慢性骨髄性白血病 (CML) は,特定の遺伝子変異と細胞機能の変化によって特徴づけられる骨髄増殖性腫瘍である.
研究 の 目的:
- 慢性骨髄性白血病 (CML) の発症と進行におけるBCAT1,BCAAアミノトランスフェラスの役割を調査する.
- CMLにおけるBCAT1発現を制御する規制メカニズムを明らかにする.
- 骨髄性白血病におけるBCAT1を標的とした治療の可能性を決定する.
主な方法:
- 人間のCMLサンプルとマウスモデルにおけるBCAT1発現の分析
- CML細胞に対するBCAT1抑制の機能的影響を評価するためのin vitroおよびin vivo実験.
- 安定同位体トレーサー実験と核磁気共鳴 (NMR) メタボロミクスで,BCAAの代謝を追跡する.
- ムサシ2 (MSI2) を含むBCAT1のアップストリームレギュレータの識別と特徴付け
主要な成果:
- BCAT1は異常に活性化され,CMLでは機能的に必要であり,白血病細胞のBCAA生成を促進します.
- BCAT1の抑制は細胞の分化を引き起こし,CMLの進行をin vitroとin vivoで阻害する.
- BCAT1のノックダウン効果はBCAA補給によって救出され,BCAA生産におけるその役割が確認されています.
- 腫瘍性RNA結合タンパク質であるMSI2は,BCAT1発現を直接上調し,MSI2-BCAT1軸を形成する.
- BCAT1の発現は,CMLと急性骨髄性白血病の患者の疾患の進行を予測する.
結論:
- MSI2- BCAT1軸は,BCAAの代謝を変化させることで,骨髄性白血病のがん進行を誘導する.
- BCAT1はCMLにおける重要な腫瘍発生因子であり,潜在的な治療標的である.
- MSI2- BCAT1経路を標的とした治療は 骨髄性白血病の治療において有望な戦略です
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