1. Functional genomic landscape of acute myeloid leukaemia
- Author
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Robert H. Collins, Deirdre Devine, Beth Wilmot, Justin Ramsdill, Erik Segerdell, Bruno C. Medeiros, Brian J. Druker, Dylan Nelson, Micaela E. Martinez, Ryan C. Johnson, Robert Schuff, Robert P. Searles, Scott Weir, James Dibb, Elie Traer, Pierrette Lo, Haijiao Zhang, Rachel Henson, Tara A. Macey, Isabel English, Cody Coblentz, Christopher A. Eide, Ceilidh Nichols, Aurora Blucher, Ryan M. Winters, David L. Wiest, Corinne Visser, Michael W. Deininger, Stephen E. Kurtz, Daniel A. Pollyea, Justin M. Watts, Amy S. Carlos, Denise C. Connolly, Andy Kaempf, Angela Rofelty, Samuel B. Luty, Rachel J. Cook, Jill Peters, Kristen Werth, Shannon K. McWeeney, Joseph Carroll, Samantha L. Savage, Ronan T. Swords, Uma Borate, Aashis Thapa, Abdusebur Jemal, Joelle Wolf, Patricia Kropf, Rebecca Smith, Tyler Sweeney, Russell T. Burke, Rachel R. Pallapati, Anna Reister Schultz, Kim Hien T. Dao, Daniel Bottomly, Cristina E. Tognon, Alexey V. Danilov, Jason M. Glover, Jason D. MacManiman, Michie Degnin, Amy Yates, Libbey White, David K. Edwards, Anupriya Agarwal, Christopher R. Cogle, Kevin Watanabe-Smith, Leylah Drusbosky, Nicola Long, Motomi Mori, Christopher S. Hourigan, Tara L. Lin, Chenwei Lin, Jacqueline Martinez, Bill H. Chang, Richie Carpenter, Stephen E. Spurgeon, Brian Junio, Marc M. Loriaux, Craig T. Jordan, Hibery Ho, Selina Qiuying Liu, Melissa L. Abel, Amanda d’Almeida, Jake Wagner, Jade Bryant, Jeffrey W. Tyner, Jessica Leonard, and Kara Johnson
- Subjects
Male ,0301 basic medicine ,Myeloid ,Gene regulatory network ,Datasets as Topic ,Genomics ,Computational biology ,Biology ,Article ,DNA Methyltransferase 3A ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,medicine ,Humans ,Exome ,DNA (Cytosine-5-)-Methyltransferases ,Molecular Targeted Therapy ,Exome sequencing ,Regulation of gene expression ,Multidisciplinary ,Serine-Arginine Splicing Factors ,Genome, Human ,Sequence Analysis, RNA ,Nuclear Proteins ,medicine.disease ,Human genetics ,3. Good health ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Core Binding Factor Alpha 2 Subunit ,Female ,Nucleophosmin - Abstract
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.
- Published
- 2018
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