急性白血病におけるENL YEATS領域による転写制御
Michael A Erb1, Thomas G Scott1, Bin E Li2,3,4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature
|February 28, 2017
まとめ
研究者らはENLが 侵襲的な急性白血病の増殖に 欠かせないことを発見しました YEATSの領域をターゲットにすることで この困難な癌の新たな治療戦略が生まれます
科学分野:
- 腫瘍学
- 分子生物学
- 遺伝学
背景:
- MLL遺伝子を伴う再発性染色体転位は融合腫瘍遺伝子を生成し,予後が悪い攻撃的な急性白血病を引き起こす.
- MLLによる白血病の現在の治療法は不十分であり,新しい治療目標の必要性を強調しています.
- 染色体調節体はMLL誘発性白血病に関与しており,転写制御に依存していることを示唆している.
研究 の 目的:
- 全ゲノムスクリーンを用いて,MLL-AF4陽性の急性白血病の増殖に不可欠な新しい遺伝子を特定する.
- 特定された遺伝子であるENLが白血病発生と転写調節におけるメカニズム的役割を明らかにする.
- ENLを標的とした治療の可能性を調査する.
主な方法:
- MLL-AF4陽性の急性白血病細胞系におけるCRISPR-Cas9機能喪失のゲノムスケールスクリーン.
- ENLの標的タンパク質分解のための化学遺伝的戦略
- ゲノム全体のRNAポリメラーゼII開始と延伸の分析
- 白血病の成長におけるYEATS染色体読者領域の役割の評価
主要な成果:
- ENLはMLL- AF4陽性急性白血病細胞の増殖に特異的に必要な遺伝子としてin vitroおよびin vivoで特定されました.
- ENLの急性枯渇は,活性遺伝子のRNAポリメラーゼII開始と延長を著しく抑制した.
- ENLのYEATS染色体読者ドメインは白血病細胞の成長に不可欠であることが判明しました.
- ENLは特定の遺伝子に不釣り合いな負荷を示し,転写ダイナミクスに影響を与えました.
結論:
- ENLはMLLによる急性白血病の重要な依存因子です.
- ENLの機能,特に YEATS領域の障害は,この攻撃的な白血病に対する有望な治療戦略です.
- これらの発見は,白血病発生におけるENLをターゲットにするためのメカニズム的根拠を提供します.
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