治療に関連した急性骨髄性白血病の起源と進化におけるTP53変異の役割

Terrence N Wong¹, Giridharan Ramsingh², Andrew L Young³

¹Department of Medicine, Division of Oncology, Washington University, St. Louis, MO.

Nature

|December 10, 2014

まとめ

化学療法は,治療に関連した白血病のTP53変異を直接引き起こしません. 代わりに,幹細胞の既存のTP53変異は抵抗性を授与し,治療後にその拡張につながります.

科学分野:

血液学ヘマトロジ
がん生物学がん生物学
遺伝学遺伝学とは

背景:

治療に関連した急性骨髄性白血病 (t-AML) と骨髄分裂症候群 (t-MDS) は,がん治療の合併症として知られています.
これらの疾患は,しばしばTP53変異と染色体異常が特徴ですが,それ以前の治療の役割は不明です.

研究の目的:

治療に関連する白血病においてTP53変異が濃縮されるメカニズムを調査する.
細胞毒性療法が直接TP53変異を誘発するか,または既にある変異を選択するかどうかを判断する.

主な方法:

22人のt-AML患者のゲノムシーケンシング.
治療前のサンプルおよび健康な個体におけるTP53変異の検出.
ネズミの骨髄キメラ実験で,化学療法を受けた後の血液生成性幹細胞/原始細胞 (HSPC) の行動を評価する.

主要な成果:

化学療法は,de novo AMLと比較して,t-AMLにおける全ゲノムにわたるDNA損傷またはトランスバーションを増加させなかった.
TP53の変異は,診断の数年前から白血病前細胞や,健康な高齢の個体で検出されました.
Tp53変異のHSPCは,マウスモデルでの化学療法後に好ましい拡張を示した.

結論:

細胞毒性治療は,TP53変異を直接誘導するものではありません.
希少なHSPCの年齢に関連するTP53変異は,化学抵抗性を授与し,治療後のクローン拡張につながります.
TP53変異の早期獲得は,t-AML/t-MDSの発症と治療への反応の低下に寄与する可能性がある.

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