DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia.
DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia.
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DOI：
10.1101/gr.269233.120
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发表时间：
2021-05
期刊：
影响因子：
7
通讯作者：
Oakes CC
中科院分区：
文献类型：
--
作者：
Giacopelli B;Wang M;Cleary A;Wu YZ;Schultz AR;Schmutz M;Blachly JS;Eisfeld AK;Mundy-Bosse B;Vosberg S;Greif PA;Claus R;Bullinger L;Garzon R;Coombes KR;Bloomfield CD;Druker BJ;Tyner JW;Byrd JC;Oakes CC
急性髓系白血病(AML)是一种分子复杂的疾病，具有异质性的肿瘤遗传学特征，涉及多种致病机制和途径。跨多个患者队列的分子数据类型的集成可能会推进当前的遗传学方法，以改进细分和对疾病生物学的理解。在这里，我们使用Illumina阵列分析了649名AML患者的全基因组DNA甲基化，并使用无偏聚类确定了13个亚型(称为“表型”)的配置。整合遗传数据显示，在大多数患者中，大多数表型与某种反复发生的突变(或组合)有关，而其他表型在很大程度上是独立的。表型在髓系分化的离散阶段显示发育受阻，揭示了保留受阻的造血干细胞样表型的表型。对DNA甲基化模式的详细分析确定了表型之间异常高甲基化和低甲基化的独特模式，影响启动子、增强子和抑制区的转录因子的参与程度各不相同。具有干细胞样甲基化特征表型的患者总体存活率较低，同时干细胞基因表达特征上调。我们进一步鉴定了一个DNA甲基化特征，涉及与Flt3-ITD突变相关的STAT基序。最后，大多数患者的DNA甲基化特征在复发时是稳定的，罕见的表型转换伴随着显性表型突变的丢失和向干细胞样甲基化模式的逆转。这些结果表明，基于DNA甲基化的分类结合了AML的重要分子特征，以揭示疾病的不同致病和生物学方面。
Acute myeloid leukemia (AML) is a molecularly complex disease characterized by heterogeneous tumor genetic profiles and involving numerous pathogenic mechanisms and pathways. Integration of molecular data types across multiple patient cohorts may advance current genetic approaches for improved subclassification and understanding of the biology of the disease. Here, we analyzed genome-wide DNA methylation in 649 AML patients using Illumina arrays and identified a configuration of 13 subtypes (termed “epitypes”) using unbiased clustering. Integration of genetic data revealed that most epitypes were associated with a certain recurrent mutation (or combination) in a majority of patients, yet other epitypes were largely independent. Epitypes showed developmental blockage at discrete stages of myeloid differentiation, revealing epitypes that retain arrested hematopoietic stem-cell-like phenotypes. Detailed analyses of DNA methylation patterns identified unique patterns of aberrant hyper- and hypomethylation among epitypes, with variable involvement of transcription factors influencing promoter, enhancer, and repressed regions. Patients in epitypes with stem-cell-like methylation features showed inferior overall survival along with up-regulated stem cell gene expression signatures. We further identified a DNA methylation signature involving STAT motifs associated with FLT3-ITD mutations. Finally, DNA methylation signatures were stable at relapse for the large majority of patients, and rare epitype switching accompanied loss of the dominant epitype mutations and reversion to stem-cell-like methylation patterns. These results show that DNA methylation-based classification integrates important molecular features of AML to reveal the diverse pathogenic and biological aspects of the disease.
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影响因子：
120.7
作者：
Gentles, Andrew J.;Plevritis, Sylvia K.;Majeti, Ravindra;Alizadeh, Ash A.
通讯作者：
Alizadeh, Ash A.
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
28.2
作者：
Glass JL;Hassane D;Wouters BJ;Kunimoto H;Avellino R;Garrett-Bakelman FE;Guryanova OA;Bowman R;Redlich S;Intlekofer AM;Meydan C;Qin T;Fall M;Alonso A;Guzman ML;Valk PJM;Thompson CB;Levine R;Elemento O;Delwel R;Melnick A;Figueroa ME
通讯作者：
Figueroa ME
影响因子：
82.9
作者：
Guryanova OA;Shank K;Spitzer B;Luciani L;Koche RP;Garrett-Bakelman FE;Ganzel C;Durham BH;Mohanty A;Hoermann G;Rivera SA;Chramiec AG;Pronier E;Bastian L;Keller MD;Tovbin D;Loizou E;Weinstein AR;Gonzalez AR;Lieu YK;Rowe JM;Pastore F;McKenney AS;Krivtsov AV;Sperr WR;Cross JR;Mason CE;Tallman MS;Arcila ME;Abdel-Wahab O;Armstrong SA;Kubicek S;Staber PB;Gönen M;Paietta EM;Melnick AM;Nimer SD;Mukherjee S;Levine RL
通讯作者：
Levine RL
影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard