幹細胞微環境におけるPtpn11活性化変異の白血病発生効果
Lei Dong1, Wen-Mei Yu1, Hong Zheng1
1Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Nature
|November 4, 2016
まとめ
骨髄の微環境内のPTPN11の活性化変異は,CCL3を増加させることで,骨髄増殖性腫瘍 (MPNs) を誘発する. CCL3をターゲットにすることで,MPNの発症を逆転させ,ヌーナン症候群における幹細胞移植の結果を改善することができる.
科学分野:
- 血液学
- 腫瘍学
- 分子生物学
背景:
- ゲルムラインPTPN11変異はヌーナン症候群を引き起こし,白血病のリスクを高める.
- PTPN11変異は,細胞自律的メカニズムを通じて若年性骨髄性白血病 (JMML) を誘発する.
- MPNにおける骨髄微環境におけるPTPN11変異の役割は不明である.
研究 の 目的:
- 骨髄の微小環境におけるPTPN11変異がMPNの発達に与える影響を調査する.
- PTPN11変異が血液形成幹細胞 (HSC) に影響するメカニズムを決定する.
- ヌーナン症候群に関連するMPNの潜在的な治療標的を特定する.
主な方法:
- 骨髄のストロマ細胞にPtpn11活性化変異があるマウスモデルを使用した.
- 造血幹細胞 (HSC) とMPNの進行に対する評価効果
- 治療の可能性を評価するためにCCL3受容体の抗体投与.
主要な成果:
- Ptpn11変異はメゼンキマ幹細胞/プロジェニータおよびオステオプロジェニータ細胞でMPNを促進する.
- 変異したPtpn11細胞はCCL3を過剰に生成し,HSCを活性化する単細胞を募集します.
- CCL3受容体の抗体投与は,MPNの発症を逆転させた.
- ドナー細胞由来MPNは,幹細胞移植後に観察されました.
結論:
- 骨髄の微小環境におけるPTPN11変異は白血病発生に決定的に寄与する.
- CCL3は,この文脈でMPNの発展と進行の重要な仲介者です.
- CCL3抗体は,ヌーナン症候群に関連したMPNおよび幹細胞移植の潜在的な治療戦略を表しています.
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