Functional genomic landscape of acute myeloid leukaemia
Jeffrey W. Tyner,Cristina E. Tognon,Cristina E. Tognon,Daniel Bottomly,Beth Wilmot,Stephen E. Kurtz,Samantha L. Savage,Nicola Long,Anna Reister Schultz,Elie Traer,Melissa L. Abel,Anupriya Agarwal,Aurora Blucher,Uma Borate,Jade Bryant,Russell T. Burke,Amy S. Carlos,Richie Carpenter,Joseph Carroll,Bill H. Chang,Cody Coblentz,Amanda d’Almeida,Rachel J. Cook,Alexey V. Danilov,Kim Hien T. Dao,Michie Degnin,Deirdre Devine,James Dibb,David K. Edwards,Christopher A. Eide,Christopher A. Eide,Isabel English,Jason M. Glover,Rachel Henson,Hibery Ho,Abdusebur Jemal,Kara Johnson,Ryan C. Johnson,Brian Junio,Andy Kaempf,Jessica Leonard,Chenwei Lin,Selina Qiuying Liu,Pierrette Lo,Marc M. Loriaux,Samuel B. Luty,Tara A. Macey,Jason D. MacManiman,Jacqueline Martinez,Motomi Mori,Dylan Nelson,Ceilidh Nichols,Jill Peters,Justin Ramsdill,Angela Rofelty,Robert Schuff,Robert P. Searles,Erik Segerdell,Rebecca Smith,Stephen E. Spurgeon,Tyler Sweeney,Aashis Thapa,Corinne Visser,Jake Wagner,Kevin Watanabe-Smith,Kristen Werth,Joelle Wolf,Libbey White,Amy Yates,Haijiao Zhang,Christopher R. Cogle,Robert H. Collins,Denise C. Connolly,Michael W. Deininger,Leylah Drusbosky,Christopher S. Hourigan,Craig T. Jordan,Patricia Kropf,Tara L. Lin,Micaela E. Martinez,Bruno C. Medeiros,Rachel R. Pallapati,Daniel A. Pollyea,Ronan T. Swords,Justin M. Watts,Scott Weir,David L. Wiest,Ryan M. Winters,Shannon K. McWeeney,Brian J. Druker,Brian J. Druker +90 more
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TLDR
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.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.read more
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CA : A Cancer Journal for Clinicians
Patrizia Agostinis,Kristian Berg,Keith A. Cengel,Thomas H. Foster,Albert W. Girotti,Sandra O. Gollnick,Stephen M. Hahn,Michael R. Hamblin,Asta Juzeniene,David Kessel,Mladen Korbelik,Johan Moan,Pawel Mroz,Dominika Nowis,Jacques Piette,Brian C. Wilson,Jakub Golab +16 more
Journal ArticleDOI
A compendium of mutational cancer driver genes.
Francisco Martínez-Jiménez,Ferran Muiños,Inés Sentís,Jordi Deu-Pons,Iker Reyes-Salazar,Claudia Arnedo-Pac,Loris Mularoni,Oriol Pich,Jose Bonet,Hanna Kranas,Abel Gonzalez-Perez,Nuria Lopez-Bigas,Nuria Lopez-Bigas +12 more
TL;DR: This Review provides a brief historical perspective of the role of cancer genes before presenting the Integrative OncoGenomics (IntOGen) platform, a bioinformatics method of mutational driver identification, which is beginning to reveal the compendium of driver genes across many tumour types as well as alluding to their tumorigenic mechanisms.
Journal ArticleDOI
Impact of Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia With Genomic Evidence of Residual Disease
Christopher S. Hourigan,Laura W. Dillon,Gege Gui,Brent R. Logan,Mingwei Fei,Jack Ghannam,Yuesheng Li,Abel Licon,Edwin P. Alyea,Asad Bashey,H. Joachim Deeg,Steven M. Devine,Hugo F. Fernandez,Sergio Giralt,Mehdi Hamadani,Alan Howard,Richard T. Maziarz,David L. Porter,Bart L. Scott,Erica D. Warlick,Marcelo C. Pasquini,Mitchell E. Horwitz +21 more
TL;DR: Evidence is provided that MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival, and models of AML MRD also showed benefit for MAC over RIC for those who tested positive.
Journal ArticleDOI
Molecular biomarkers in acute myeloid leukemia
TL;DR: This review summarizes the most relevant molecular (genetic, epigenetic, and protein) biomarkers associated with acute myeloid leukemia and discusses their clinical importance in terms of risk prediction, diagnosis and prognosis.
Journal ArticleDOI
Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia.
Shanshan Pei,Daniel A. Pollyea,Annika Gustafson,Brett M. Stevens,Mohammad Minhajuddin,Rui Fu,Kent Riemondy,Austin E. Gillen,Ryan M. Sheridan,Jihye Kim,James C. Costello,Maria L. Amaya,Anagha Inguva,Amanda Winters,Haobin Ye,Anna Krug,Courtney L. Jones,Biniam Adane,Nabilah Khan,J Ponder,Jeffrey Schowinsky,Diana Abbott,Andrew Hammes,Jason R. Myers,John M. Ashton,Travis Nemkov,Angelo D'Alessandro,Jonathan A. Gutman,Haley E. Ramsey,Michael R. Savona,Clayton A. Smith,Craig T. Jordan +31 more
TL;DR: It is concluded that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation, and it is proposed that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis.
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