Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.
Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.
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DOI：
10.1038/nature13968
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发表时间：
2015-02-26
期刊：
影响因子：
64.8
通讯作者：
Wilson, Richard K.
中科院分区：
文献类型：
--
作者：
Wong, Terrence N.;Ramsingh, Giridharan;Young, Andrew L.;Miller, Christopher A.;Touma, Waseem;Welch, John S.;Lamprecht, Tamara L.;Shen, Dong;Hundal, Jasreet;Fulton, Robert S.;Heath, Sharon;Baty, Jack D.;Klco, Jeffery M.;Ding, Li;Mardis, Elaine R.;Westervelt, Peter;DiPersio, John F.;Walter, Matthew J.;Graubert, Timothy A.;Ley, Timothy J.;Druley, Todd E.;Link, Daniel C.;Wilson, Richard K.
治疗相关性急性髓性白血病（t-AML）和治疗相关性骨髓增生异常综合征（t-MDS）是公认的细胞毒性化疗和/或放疗的并发症。将t-AML与新生aml区分出来有几个特征，包括tp53突变的发生率较高，5号或7号染色体异常，复杂的细胞遗传学以及对化疗的反应降低。然而，目前尚不清楚先前暴露于细胞毒性治疗如何影响白血病的发生。特别是，htp53突变在t-AML/t-MDS中选择性富集的机制尚不清楚。在这里，通过对22例t-AML患者的基因组测序，我们发现t-AML和de novoAML中体细胞单核苷酸变异的总数和化疗相关转化的百分比相似，这表明先前的化疗不会诱导全基因组DNA损伤。我们确定了4例t-AML/t-MDS患者，在诊断时发现的确切ttp53突变在t-AML/t-MDS发生前3-6年在动员的血液白细胞或骨髓中也以低频率（0.003-0.7%）存在，其中包括2例在任何化疗前检测到相关ttp53突变的患者。此外，在健康的未接受化疗的老年人的少量外周血细胞中发现了功能性的altp53突变。最后，在含有野生型和tp53 +/−造血干细胞/祖细胞（HSPCs）的小鼠骨髓嵌合体中，tp53 +/−HSPCs在暴露于化疗后优先扩增。这些数据表明细胞毒性治疗不会直接诱导etp53突变。相反，他们支持一种模型，即携带与年龄相关的tp53突变的罕见HSPCs对化疗具有抗性，并且在治疗后优先扩大。在HSPC克隆中早期获得tp53突变可能导致t-AML/t-MDS患者常见的细胞遗传学异常和化疗反应差。
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML fromde novoAML, including a higher incidence ofTP53mutations,, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by whichTP53mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML andde novoAML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exactTP53mutation found at diagnosis was also present at low frequencies (0.003–0.7%) in mobilized blood leukocytes or bone marrow 3–6 years before the development of t-AML/t-MDS, including two cases in which the relevantTP53mutation was detected before any chemotherapy. Moreover, functionalTP53mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type andTp53+/−haematopoietic stem/progenitor cells (HSPCs), theTp53+/−HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induceTP53mutations. Rather, they support a model in which rare HSPCs carrying age-relatedTP53mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition ofTP53mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.
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影响因子：
9.8
作者：
Marusyk A;Porter CC;Zaberezhnyy V;DeGregori J
通讯作者：
DeGregori J
影响因子：
64.5
作者：
Welch JS;Ley TJ;Link DC;Miller CA;Larson DE;Koboldt DC;Wartman LD;Lamprecht TL;Liu F;Xia J;Kandoth C;Fulton RS;McLellan MD;Dooling DJ;Wallis JW;Chen K;Harris CC;Schmidt HK;Kalicki-Veizer JM;Lu C;Zhang Q;Lin L;O'Laughlin MD;McMichael JF;Delehaunty KD;Fulton LA;Magrini VJ;McGrath SD;Demeter RT;Vickery TL;Hundal J;Cook LL;Swift GW;Reed JP;Alldredge PA;Wylie TN;Walker JR;Watson MA;Heath SE;Shannon WD;Varghese N;Nagarajan R;Payton JE;Baty JD;Kulkarni S;Klco JM;Tomasson MH;Westervelt P;Walter MJ;Graubert TA;DiPersio JF;Ding L;Mardis ER;Wilson RK
通讯作者：
Wilson RK
p53 脉冲介导的细胞命运决定
DOI：
10.1073/pnas.0813088106
发表时间：
2009-07-28
影响因子：
11.1
作者：
Zhang, Xiao-Peng;Liu, Feng;Wang, Wei
通讯作者：
Wang, Wei
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
23.9
作者：
Bondar T;Medzhitov R
通讯作者：
Medzhitov R