在复发性急性淋巴细胞白血病中的CREBBP突变.
Charles G Mullighan1, Jinghui Zhang, Lawryn H Kasper
1Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Nature
|March 11, 2011
概括
复发性急性淋巴细胞白血病 (ALL) 在年轻人中是致命的. 基因分析揭示了CREBBP和其他基因的突变,这些基因驱动治疗耐药性和疾病复发.
科学领域:
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- 复发性急性淋巴细胞白血病 (ALL) 是年轻人癌症死亡的主要原因.
- 导致ALL治疗失败的潜在生物学因素尚不清楚.
- 之前的研究发现了结构性DNA变化和从诊断到ALL复发的遗传进化.
研究的目的:
- 为了识别复发ALL的新型DNA序列突变.
- 研究基因变异在治疗耐药性和复发中的作用.
- 分析已识别的突变对基因调节的功能影响.
主要方法:
- 从23名ALL患者的匹配诊断和复发样本中重新测序300个基因.
- 对71例诊断复发病例和270例非复发急性白血病病例的扩展队列的分析.
- 功能性测试,以评估突变对基因素乙化和基因表达的影响.
主要成果:
- 在32个基因中确定了52个体质非同义突变,包括CREBBP,NCOR1,ERG和SPI1.1中的新突变.
- 在18.3%的复发病例中发现了CREBBP突变 (序列或删除),影响了组织酸转移酶活性.
- 观察到在复发时获得的突变有时存在于诊断时的亚克隆中,这表明在治疗耐药性中发挥了作用.
结论:
- 针对转录和表观遗传调节的突变,特别是在CREBBP中,是ALL中抗性的重要机制.
- 这些发现扩大了对白血病遗传变化的理解.
- 识别这些突变可能为复发ALL提供新的治疗点.
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