Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia.
Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia.
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DOI：
10.1038/s41467-021-27472-5
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发表时间：
2021-12-13
影响因子：
16.6
通讯作者：
Majeti R
中科院分区：
文献类型：
--
作者：
Benard BA;Leak LB;Azizi A;Thomas D;Gentles AJ;Majeti R
克隆异质性对急性髓系白血病患者疾病行为或药物反应的影响仍然知之甚少。利用2829名患者的队列，我们确定了与临床特征和药物敏感性相关的克隆性特征。7个突变(包括NRAS和TET2)的高变异等位基因频率与预后不良相关；GATA2变异等位基因频率升高与较好的预后相关。临床特征，如白细胞计数和原始细胞百分比与突变的亚克隆丰度相关，如TP53和IDH1。此外，粘附素突变发生在NPM1之前，或者转录因子突变发生在剪接因子突变之前，患者的生存期较短。令人惊讶的是，克隆进化的分支模式与更好的临床结果相关。最后，几个突变(包括NRAS和IDH1)根据它们的亚克隆丰度预测药物敏感性。总之，这些结果证明了评估克隆异质性的重要性，并对预后和可操作的治疗生物标记物进行了暗示。个别研究未能得出克隆异质性与急性髓系白血病(AML)治疗反应之间的明确联系。在这里，作者汇总了多个AML队列，并能够将体细胞突变的克隆性丰度与临床结果和药物敏感性相关联。
The impact of clonal heterogeneity on disease behavior or drug response in acute myeloid leukemia remains poorly understood. Using a cohort of 2,829 patients, we identify features of clonality associated with clinical features and drug sensitivities. High variant allele frequency for 7 mutations (including NRAS and TET2) associate with dismal prognosis; elevated GATA2 variant allele frequency correlates with better outcomes. Clinical features such as white blood cell count and blast percentage correlate with the subclonal abundance of mutations such as TP53 and IDH1. Furthermore, patients with cohesin mutations occurring before NPM1, or transcription factor mutations occurring before splicing factor mutations, show shorter survival. Surprisingly, a branched pattern of clonal evolution is associated with superior clinical outcomes. Finally, several mutations (including NRAS and IDH1) predict drug sensitivity based on their subclonal abundance. Together, these results demonstrate the importance of assessing clonal heterogeneity with implications for prognosis and actionable biomarkers for therapy. Individual studies have been underpowered to draw clear associations between clonal heterogeneity and response to therapy in acute myeloid leukemia (AML). Here, the authors aggregate multiple AML cohorts and are able to correlate the clonal abundance of somatic mutations with clinical outcomes and drug sensitivity.
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影响因子：
82.9
作者：
Bernard E;Nannya Y;Hasserjian RP;Devlin SM;Tuechler H;Medina-Martinez JS;Yoshizato T;Shiozawa Y;Saiki R;Malcovati L;Levine MF;Arango JE;Zhou Y;Solé F;Cargo CA;Haase D;Creignou M;Germing U;Zhang Y;Gundem G;Sarian A;van de Loosdrecht AA;Jädersten M;Tobiasson M;Kosmider O;Follo MY;Thol F;Pinheiro RF;Santini V;Kotsianidis I;Boultwood J;Santos FPS;Schanz J;Kasahara S;Ishikawa T;Tsurumi H;Takaori-Kondo A;Kiguchi T;Polprasert C;Bennett JM;Klimek VM;Savona MR;Belickova M;Ganster C;Palomo L;Sanz G;Ades L;Della Porta MG;Elias HK;Smith AG;Werner Y;Patel M;Viale A;Vanness K;Neuberg DS;Stevenson KE;Menghrajani K;Bolton KL;Fenaux P;Pellagatti A;Platzbecker U;Heuser M;Valent P;Chiba S;Miyazaki Y;Finelli C;Voso MT;Shih LY;Fontenay M;Jansen JH;Cervera J;Atsuta Y;Gattermann N;Ebert BL;Bejar R;Greenberg PL;Cazzola M;Hellström-Lindberg E;Ogawa S;Papaemmanuil E
通讯作者：
Papaemmanuil E
在健康个体中预测急性髓样白血病的风险。
影响因子：
64.8
作者：
Abelson S;Collord G;Ng SWK;Weissbrod O;Mendelson Cohen N;Niemeyer E;Barda N;Zuzarte PC;Heisler L;Sundaravadanam Y;Luben R;Hayat S;Wang TT;Zhao Z;Cirlan I;Pugh TJ;Soave D;Ng K;Latimer C;Hardy C;Raine K;Jones D;Hoult D;Britten A;McPherson JD;Johansson M;Mbabaali F;Eagles J;Miller JK;Pasternack D;Timms L;Krzyzanowski P;Awadalla P;Costa R;Segal E;Bratman SV;Beer P;Behjati S;Martincorena I;Wang JCY;Bowles KM;Quirós JR;Karakatsani A;La Vecchia C;Trichopoulou A;Salamanca-Fernández E;Huerta JM;Barricarte A;Travis RC;Tumino R;Masala G;Boeing H;Panico S;Kaaks R;Krämer A;Sieri S;Riboli E;Vineis P;Foll M;McKay J;Polidoro S;Sala N;Khaw KT;Vermeulen R;Campbell PJ;Papaemmanuil E;Minden MD;Tanay A;Balicer RD;Wareham NJ;Gerstung M;Dick JE;Brennan P;Vassiliou GS;Shlush LI
通讯作者：
Shlush LI
影响因子：
20.3
作者：
Lindsley, R. Coleman;Mar, Brenton G.;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.
影响因子：
30.8
作者：
Corces, M. Ryan;Buenrostro, Jason D.;Wu, Beijing;Greenside, Peyton G.;Chan, Steven M.;Koenig, Julie L.;Snyder, Michael P.;Pritchard, Jonathan K.;Kundaje, Anshul;Gkeenleaf, William J.;Majeti, Ravindra;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
急性髓样白血病中克隆特异性残留疾病的精度和预后价值。
影响因子：
10.1
作者：
Hirsch P;Tang R;Abermil N;Flandrin P;Moatti H;Favale F;Suner L;Lorre F;Marzac C;Fava F;Mamez AC;Lapusan S;Isnard F;Mohty M;Legrand O;Douay L;Bilhou-Nabera C;Delhommeau F
通讯作者：
Delhommeau F