Bリンパ性転写因子の代謝ゲートキーパー機能
Lai N Chan1,2, Zhengshan Chen1,2, Daniel Braas3
1Department of Systems Biology, Beckman Research Institute and City of Hope National Medical Center, Pasadena, California 91016, USA.
Nature
|February 14, 2017
まとめ
Bリンパ球の転写因子PAX5とIKZF1は,代謝ゲートキーパーとして作用し,B細胞発達のエネルギー供給を制限する. B型前急性リンパ性白血病 (ALL) の場合,それらの喪失はエネルギー危機を引き起こし,治療標的を強調する.
科学分野:
- 分子生物学
- 細胞の代謝
- 癌 生物学
背景:
- Bリンパ球転写因子PAX5とIKZF1は,B細胞発育に不可欠である.
- PAX5とIKZF1の変異はB細胞前急性リンパ性白血病 (ALL) で頻繁に見られるが,その役割は不明である.
- これらの要因の役割を理解することは,標的型療法にとって極めて重要です.
研究 の 目的:
- Bリンパ球細胞における細胞代謝の調節におけるPAX5とIKZF1の役割を解明する.
- これらの転写因子がALLにおけるエネルギー供給と細胞運命を影響するメカニズムを特定する.
- B ALL前期における代謝経路を標的とした治療戦略を探る.
主な方法:
- 染色体免疫降水とシーケンシング (ChIP-seq) とRNAシーケンシング.
- グルコースの吸収とATPレベル測定を含む代謝分析
- CRISPR/Cas9スクリーニングと,トランスジェニックのB型ALLマウスモデルを用いたin vivo研究.
主要な成果:
- PAX5とIKZF1は,グルコースとエネルギー供給を制限する代謝プログラムを実行し,エネルギー欠乏とAMPKの活性化につながります.
- B ALL前におけるPAX5/ IKZF1機能の喪失は,グルコースの吸収とATPのレベルを増加させる.
- NR3C1,TXNIP,CNR2は,この代謝制限の主要なメディエーターとして特定されました.
- ターゲティングTXNIP,CNR2,AMPKはグルココルチコイドと相乗効果があり,治療的な可能性を秘めています.
結論:
- 細胞のATPレベルを制御し,悪性変異を防ぐ.
- これらの代謝ゲートキープの調節不良は,B型ALLの病原性における重要な出来事です.
- 代謝経路,特にTXNIP,CNR2,AMPKを標的とした治療は,ALLの有望な治療法です.
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