Functional genomic landscape of acute myeloid leukaemia

被引：933

作者：

Tyner, Jeffrey W. ^{[1
,2
]}

Tognon, Cristina E. ^{[2
,3
,4
]}

Bottomly, Daniel ^{[2
,5
]}

Wilmot, Beth ^{[2
,5
,6
]}

Kurtz, Stephen E. ^{[2
,3
]}

Savage, Samantha L. ^{[1
,2
]}

Long, Nicola ^{[2
,3
]}

Schultz, Anna Reister ^{[1
,2
]}

Traer, Elie ^{[2
]}

Abel, Melissa ^{[1
,2
]}

Agarwal, Anupriya ^{[2
,7
]}

Blucher, Aurora ^{[2
,5
]}

Borate, Uma ^{[2
,3
]}

Bryant, Jade ^{[1
,2
]}

Burke, Russell ^{[2
,3
]}

Carlos, Amy ^{[2
,8
]}

Carpenter, Richie ^{[2
,3
]}

Carroll, Joseph ^{[2
,9
]}

Chang, Bill H. ^{[2
,10
]}

Coblentz, Cody ^{[2
,3
]}

d'Almeida, Amanda ^{[1
,2
]}

Cook, Rachel ^{[2
,3
]}

Danilov, Alexey ^{[2
,3
]}

Dao, Kim-Hien T. ^{[2
,3
]}

Degnin, Michie ^{[2
,3
]}

Devine, Deirdre ^{[2
,3
]}

Dibb, James ^{[2
,3
]}

Edwards, David K., V ^{[1
,2
]}

Eide, Christopher A. ^{[2
,3
,4
]}

English, Isabel ^{[2
,3
]}

Glover, Jason ^{[2
,10
]}

Henson, Rachel ^{[2
,8
]}

Ho, Hibery ^{[2
,3
]}

Jemal, Abdusebur ^{[2
,10
]}

Johnson, Kara ^{[2
,3
]}

Johnson, Ryan ^{[2
,3
]}

Junio, Brian ^{[2
,3
]}

Kaempf, Andy ^{[2
,11
]}

Leonard, Jessica ^{[2
,3
]}

Lin, Chenwei ^{[2
,8
]}

Liu, Selina Qiuying ^{[2
,3
]}

Lo, Pierrette ^{[2
,3
]}

Loriaux, Marc M. ^{[2
,12
]}

Luty, Samuel ^{[2
,3
]}

Macey, Tara ^{[2
,3
]}

MacManiman, Jason ^{[1
,2
]}

Martinez, Jacqueline ^{[1
,2
]}

Mori, Motomi ^{[2
,11
,13
]}

Nelson, Dylan ^{[14
]}

Nichols, Ceilidh ^{[2
,3
]}

机构：

[1] Oregon Hlth & Sci Univ, Dept Cell Dev & Canc Biol, Portland, OR 97201 USA

[2] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[3] Oregon Hlth & Sci Univ, Dept Med, Div Hematol & Med Oncol, Portland, OR 97201 USA

[4] Howard Hughes Med Inst, Portland, OR USA

[5] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Div Bioinformat & Computat Biol, Portland, OR 97201 USA

[6] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Portland, OR 97201 USA

[7] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA

[8] Oregon Hlth & Sci Univ, Integrated Genom Labs, Portland, OR 97201 USA

[9] Oregon Hlth & Sci Univ, Technol Transfer & Business Dev, Portland, OR 97201 USA

[10] Oregon Hlth & Sci Univ, Dept Pediat, Div Hematol & Oncol, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97201 USA

[11] Oregon Hlth & Sci Univ, Biostat Shared Resource, Portland, OR 97201 USA

[12] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA

[13] Oregon Hlth & Sci Univ, Portland State Univ, Sch Publ Hlth, Portland, OR 97201 USA

[14] Oregon State Univ, High Throughput Screening Serv Lab, Corvalis, OR USA

[15] Univ Florida, Dept Med, Div Hematol & Oncol, Gainesville, FL USA

[16] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Hematol Oncol, Dallas, TX 75390 USA

[17] Fox Chase Canc Ctr, Mol Therapeut Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[18] Fox Chase Canc Ctr, Biosample Repository Facil, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[19] Univ Utah, Dept Internal Med, Div Hematol & Hematol Malignancies, Salt Lake City, UT 84112 USA

[20] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA

[21] Univ Colorado, Div Hematol, Denver, CO 80202 USA

[22] Fox Chase Canc Ctr, Bone Marrow Transplant Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[23] Univ Kansas, Div Hematol Malignancies & Cellular Therapeut, Kansas City, KS USA

[24] Univ Miami, Sylvester Comprehens Canc Ctr, Clin Res Serv, Miami, FL USA

[25] Stanford Univ, Dept Med Hematol, Stanford, CA 94305 USA

[26] Univ Miami, Dept Hematol, Miami Sylvester Comprehens Canc Ctr, Miami, FL USA

[27] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA

[28] Univ Kansas, Med Ctr, Dept Med, Div Med Oncol, Kansas City, KS 66103 USA

[29] Fox Chase Canc Ctr, Blood Cell Dev & Funct Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA

来源：

NATURE | 2018年 / 562卷 / 7728期

基金：

美国国家卫生研究院;

关键词：

INTERNAL TANDEM DUPLICATION; TRANS-RETINOIC ACID; MYELODYSPLASTIC SYNDROME; CLONAL HEMATOPOIESIS; GENE-EXPRESSION; FLT3; INHIBITOR; TET2; MUTATIONS; CANCER; AML; PHARMACOKINETICS;

D O I：

10.1038/s41586-018-0623-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

引用

页码：526 / +

页数：21

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