CREBBP mutations in relapsed acute lymphoblastic leukaemia.
CREBBP mutations in relapsed acute lymphoblastic leukaemia.
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DOI：
10.1038/nature09727
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发表时间：
2011-03-10
期刊：
影响因子：
64.8
通讯作者：
Downing, James R.
中科院分区：
文献类型：
--
作者：
Mullighan, Charles G.;Zhang, Jinghui;Kasper, Lawryn H.;Lerach, Stephanie;Payne-Turner, Debbie;Phillips, Letha A.;Heatley, Sue L.;Holmfeldt, Linda;Collins-Underwood, J. Racquel;Ma, Jing;Buetow, Kenneth H.;Pui, Ching-Hon;Baker, Sharyn D.;Brindle, Paul K.;Downing, James R.
复发性急性淋巴细胞白血病（ALL）是年轻人因疾病死亡的主要原因，但治疗失败的生物学决定因素仍然知之甚少。最近对ALL结构DNA改变的全基因组分析已经确定了针对关键细胞通路的多个亚微观体细胞突变，并证明了从诊断到复发的遗传改变的实质性演变。然而，尚未对ALL的序列突变进行详细分析。为了鉴定复发性ALL的新突变，我们对23例ALL患者的诊断和复发样本中的300个基因进行了重新测序。在32个基因中发现了52个体细胞非同义突变，其中许多是新的，包括转录共激活因子CREBBP和NCOR1，转录因子ERG， SPI1， TCF4和TCF7L2， Ras信号通路组分，组蛋白基因，参与组蛋白修饰的基因（CREBBP和CTCF），以及先前被证明是ALL中重复DNA拷贝数改变的靶基因。对71例诊断复发病例和270例未复发的急性白血病病例的扩展队列分析发现，18.3%的复发病例具有编码转录辅助激活因子和组蛋白乙酰转移酶（HAT） creb结合蛋白（CBP）的CREBBP序列或缺失突变。这些突变要么在诊断时出现，要么在复发时获得，并导致等位基因截断或HAT结构域保守残基的有害替换。功能上，这些突变破坏了CREBBP靶点的组蛋白乙酰化和转录调控，包括糖皮质激素应答基因。在诊断时的亚克隆中检测到复发时获得的几个突变，表明这些突变可能赋予了对治疗的抗性。这些结果扩展了白血病遗传改变的范围，并确定了靶向转录和表观遗传调控的突变是ALL耐药的一种机制。
Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biologic determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse. However, detailed analysis of sequence mutations in ALL has not been performed. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase (HAT) CREB-binding protein (CBP). The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the HAT domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.
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影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
DOI：
10.1002/ajmg.1320560125
发表时间：
1995-03-13
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
MILLER, RW;RUBINSTEIN, JH
通讯作者：
RUBINSTEIN, JH
影响因子：
64.8
作者：
Mullighan, Charles G.;Goorha, Salil;Downing, James R.
通讯作者：
Downing, James R.
影响因子：
14.9
作者：
Bordoli, L;Hüsser, S;Eckner, R
通讯作者：
Eckner, R
影响因子：
11.4
作者：
Kuiper, R. P.;Schoenmakers, E. F. P. M.;Hoogerbrugge, P. M.
通讯作者：
Hoogerbrugge, P. M.