TY - JOUR
T1 - Functional genomic landscape of acute myeloid leukaemia
AU - Tyner, Jeffrey W.
AU - Tognon, Cristina E.
AU - Bottomly, Daniel
AU - Wilmot, Beth
AU - Kurtz, Stephen
AU - Savage, Samantha L.
AU - Long, Nicola
AU - Schultz, Anna Reister
AU - Traer, Elie
AU - Abel, Melissa
AU - Agarwal, Anupriya
AU - Blucher, Aurora
AU - Borate, Uma
AU - Bryant, Jade
AU - Burke, Russell
AU - Carlos, Amy
AU - Carpenter, Richie
AU - Carroll, Joseph
AU - Chang, Bill H.
AU - Coblentz, Cody
AU - d’Almeida, Amanda
AU - Cook, Rachel
AU - Danilov, Alexey
AU - Dao, Kim-Hien
AU - Degnin, Michie
AU - Devine, Deirdre
AU - Dibb, James
AU - Edwards, David K.
AU - Eide, Christopher A.
AU - English, Isabel
AU - Glover, Jason
AU - Henson, Rachel
AU - Ho, Hibery
AU - Jemal, Abdusebur
AU - Johnson, Kara
AU - Johnson, Ryan
AU - Junio, Brian
AU - Kaempf, Andy
AU - Leonard, Jessica
AU - Lin, Chenwei
AU - Liu, Selina Qiuying
AU - Lo, Pierrette
AU - Loriaux, Marc M.
AU - Luty, Samuel
AU - Macey, Tara
AU - MacManiman, Jason
AU - Martinez, Jacqueline
AU - Mori, Motomi (Tomi)
AU - Nelson, Dylan
AU - Nichols, Ceilidh
AU - Peters, Jill
AU - Ramsdill, Justin
AU - Rofelty, Angela
AU - Schuff, Robert
AU - Searles, Robert
AU - Segerdell, Erik
AU - Smith, Rebecca L.
AU - Spurgeon, Stephen E.
AU - Sweeney, Tyler
AU - Thapa, Aashis
AU - Visser, Corinne
AU - Wagner, Jake
AU - Watanabe-Smith, Kevin
AU - Werth, Kristen
AU - Wolf, Joelle
AU - White, Libbey
AU - Yates, Amy
AU - Zhang, Haijiao
AU - Cogle, Christopher R.
AU - Collins, Robert H.
AU - Connolly, Denise C.
AU - Deininger, Michael W.
AU - Drusbosky, Leylah
AU - Hourigan, Christopher S.
AU - Jordan, Craig T.
AU - Kropf, Patricia
AU - Lin, Tara L.
AU - Martinez, Micaela E.
AU - Medeiros, Bruno C.
AU - Pallapati, Rachel R.
AU - Pollyea, Daniel A.
AU - Swords, Ronan T.
AU - Watts, Justin M.
AU - Weir, Scott J.
AU - Wiest, David L.
AU - Winters, Ryan M.
AU - McWeeney, Shannon K.
AU - Druker, Brian J.
N1 - Funding Information:
Acknowledgements We thank all of our patients at all sites for donating precious time and tissue. DNA and RNA quality assessments, library creation and short read sequencing assays were performed by the OHSU Massively Parallel Sequencing Shared Resource. S. Sheela, C. Lai, K. Lindblad and K. Oetjen helped with study coordination at NIH. B. Sawicki and C. Cline helped with study coordination at the University of Florida. S. Ravencroft helped with patient sample shipping and data entry and K. Schorno provided project management and support of activities at the University of Kansas Cancer Center. J. Taw helped with patient sample shipping and S. Patel helped with data entry at Stanford University. Funding for this project was provided, in part, by a Therapy Acceleration Grant to B.J.D. and J.W.T. from The Leukemia & Lymphoma Society and by support provided by the Knight Cancer Research Institute (Oregon Health & Science University, OHSU). Supported by grants from the National Cancer Institute (1U01CA217862, 1U54CA224019, 1U01CA214116, 3P30CA069533-18S5) and NIH/NCATS CTSA UL1TR002369 (S.K.M., B.W.). A.S.B. was supported by the National Library of Medicine Informatics Training Grant (T15LM007088). J.W.T. received grants from the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research, and the National Cancer Institute (1R01CA183947). C.R.C. received a Scholar in Clinical Research Award from The Leukemia & Lymphoma Society (2400-13), was distinguished with a Pierre Chagnon Professorship in Stem Cell Biology and Blood & Marrow Transplant and a UF Research Foundation Professorship. This work was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health.
Funding Information:
Competing interests J.W.T. receives research support from Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Seattle Genetics, Syros and Takeda, and is a co-founder of Vivid Biosciences. M.W.D. serves on the advisory boards of and/or as a consultant for Novartis, Incyte and BMS, and receives research funding from BMS and Gilead. C.S.H. receives research funding from Merck. T.L.L. consults for Jazz Pharmaceuticals and receives research funding from Tolero, Gilead, Precient, Ono, Bio-Path, Mateon, Genentech/Roche, Trovagene, Abbvie, Pfizer, Celgene, Imago, Astellas, Karyopharm, Seattle Genetics and Incyte. D.A.P. receives research funding from Pfizer and Agios and served on the advisory boards of Pfizer, Celyad, Agios, Celgene, AbbVie, Argenx, Takeda and Servier. B.J.D. serves on the advisory boards of Gilead, Aptose, and Blueprint Medicines and is a principal investigator or coinvestigator on Novartis and BMS clinical trials. The Oregon Health & Science University (on behalf of B.J.D.) has contracts with these companies to pay for patient costs, nurse and data manager salaries and institutional overhead. B.J.D. does not derive salary, nor does his laboratory receive funds from these contracts. The authors certify that all compounds tested in this study were chosen without input from any of the industry partners.
Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2018/10/25
Y1 - 2018/10/25
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-018-0623-z
DO - 10.1038/s41586-018-0623-z
M3 - Article
C2 - 30333627
AN - SCOPUS:85055455410
SN - 0028-0836
VL - 562
SP - 526
EP - 531
JO - Nature
JF - Nature
IS - 7728
ER -