Functional genomic landscape of acute myeloid leukaemia,Nature

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Functional genomic landscape of acute myeloid leukaemia
Nature ( IF 50.5 ) Pub Date : 2018-10-01 , DOI: 10.1038/s41586-018-0623-z
Jeffrey W Tyner _{1,

2} , Cristina E Tognon _{2,

3,

4} , Daniel Bottomly _{2,

5} , Beth Wilmot _{2,

5,

6} , Stephen E Kurtz _{2,

3} , Samantha L Savage _{1,

2} , Nicola Long _{2,

3} , Anna Reister Schultz _{1,

2} , Elie Traer _{2,

3} , Melissa Abel _{1,

2} , Anupriya Agarwal _{2,

7} , Aurora Blucher _{2,

5} , Uma Borate _{2,

3} , Jade Bryant _{1,

2} , Russell Burke _{2,

3} , Amy Carlos _{2,

8} , Richie Carpenter _{2,

3} , Joseph Carroll _{2,

9} , Bill H Chang _{2,

10} , Cody Coblentz _{2,

3} , Amanda d'Almeida _{1,

2} , Rachel Cook _{2,

3} , Alexey Danilov _{2,

3} , Kim-Hien T Dao _{2,

3} , Michie Degnin _{2,

3} , Deirdre Devine _{2,

3} , James Dibb _{2,

3} , David K Edwards _{1,

2} , Christopher A Eide _{2,

3,

4} , Isabel English _{2,

3} , Jason Glover _{2,

10} , Rachel Henson _{2,

8} , Hibery Ho _{2,

3} , Abdusebur Jemal _{2,

10} , Kara Johnson _{2,

3} , Ryan Johnson _{2,

3} , Brian Junio _{2,

3} , Andy Kaempf _{2,

11} , Jessica Leonard _{2,

3} , Chenwei Lin _{2,

8} , Selina Qiuying Liu _{2,

3} , Pierrette Lo _{2,

3} , Marc M Loriaux _{2,

12} , Samuel Luty _{2,

3} , Tara Macey _{2,

3} , Jason MacManiman _{1,

2} , Jacqueline Martinez _{1,

2} , Motomi Mori _{2,

11,

13} , Dylan Nelson ₁₄ , Ceilidh Nichols _{2,

3} , Jill Peters _{2,

3} , Justin Ramsdill _{5,

6} , Angela Rofelty _{1,

2} , Robert Schuff _{5,

6} , Robert Searles _{2,

8} , Erik Segerdell _{2,

5} , Rebecca L Smith _{2,

3} , Stephen E Spurgeon _{2,

3} , Tyler Sweeney _{2,

3} , Aashis Thapa _{2,

3} , Corinne Visser _{2,

3} , Jake Wagner _{2,

3} , Kevin Watanabe-Smith _{2,

3} , Kristen Werth _{2,

3} , Joelle Wolf _{2,

10} , Libbey White _{2,

5} , Amy Yates _{5,

6} , Haijiao Zhang _{1,

2} , Christopher R Cogle ₁₅ , Robert H Collins ₁₆ , Denise C Connolly _{17,

18} , Michael W Deininger ₁₉ , Leylah Drusbosky ₁₅ , Christopher S Hourigan ₂₀ , Craig T Jordan ₂₁ , Patricia Kropf ₂₂ , Tara L Lin ₂₃ , Micaela E Martinez ₂₄ , Bruno C Medeiros ₂₅ , Rachel R Pallapati ₂₄ , Daniel A Pollyea ₂₁ , Ronan T Swords ₂₆ , Justin M Watts ₂₆ , Scott J Weir _{27,

28} , David L Wiest ₂₉ , Ryan M Winters ₁₈ , Shannon K McWeeney _{2,

5,

6} , Brian J Druker _{2,

3,

4}

Affiliation

Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
Howard Hughes Medical Institute, Portland, OR, USA.
Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA.
Oregon Clinical & Translational Research Institute, Oregon Health & Science University, Portland, OR, USA.
Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
Integrated Genomics Laboratories, Oregon Health & Science University, Portland, OR, USA.
Technology Transfer & Business Development, Oregon Health & Science University, Portland, OR, USA.
Division of Hematology and Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
Biostatistics Shared Resource, Oregon Health & Science University, Portland, OR, USA.
Dapartment of Pathology, Oregon Health & Science University, Portland, OR, USA.
Oregon Health & Science University-Portland State University School of Public Health, Portland, OR, USA.
High-Throughput Screening Services Laboratory, Oregon State University, Corvalis, OR, USA.
Department of Medicine, Division of Hematology and Oncology, University of Florida, Gainesville, FL, USA.
Department of Internal Medicine/Hematology Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Fox Chase Cancer Center Biosample Repository Facility, Philadelphia, PA, USA.
Division of Hematology & Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Division of Hematology, University of Colorado, Denver, CO, USA.
Bone Marrow Transplant Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas, Kansas City, KS, USA.
Clinical Research Services, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA.
Department of Medicine-Hematology, Stanford University, Stanford, CA, USA.
Department of Hematology, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA.
Department of Toxicology, Pharmacology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Medicine, Division of Medical Oncology, University of Kansas Medical Center, Kansas City, KS, USA.
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA.

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.Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

中文翻译：

急性髓系白血病的功能基因组景观

由于患者体内和患者之间的突变模式复杂，并且缺乏针对大多数突变事件的药物，因此对急性髓系白血病（AML）实施靶向治疗一直具有挑战性。在此，我们报告了 Beat AML 项目对从 562 名患者收集的 672 份肿瘤标本进行的队列研究的初步结果。我们使用全外显子组测序、RNA 测序和离体药物敏感性分析来评估这些样本。我们的数据揭示了以前在 AML 中未检测到的突变事件。我们表明对药物的反应与突变状态相关，包括特定于组合突变事件的药物敏感性实例。与 RNA 测序的整合还揭示了基因表达特征，可以预测特定基因网络在药物反应中的作用。总的来说，我们生成了一个数据集（可通过 Beat AML 数据查看器 (Vizome) 访问），可用于对 AML 生物学进行临床、基因组、转录组和功能分析。对急性髓系白血病患者样本的分析表明，药物反应与突变状态和基因表达有关；生成的数据集为该疾病的未来临床和功能研究提供了基础。

更新日期：2018-10-01

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