Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates....

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Published in:Cancer cell Vol. 40; no. 8; p. 850
Main Authors: Bottomly, Daniel, Long, Nicola, Schultz, Anna Reister, Kurtz, Stephen E, Tognon, Cristina E, Johnson, Kara, Abel, Melissa, Agarwal, Anupriya, Avaylon, Sammantha, Benton, Erik, Blucher, Aurora, Borate, Uma, Braun, Theodore P, Brown, Jordana, Bryant, Jade, Burke, Russell, Carlos, Amy, Chang, Bill H, Cho, Hyun Jun, Christy, Stephen, Coblentz, Cody, Cohen, Aaron M, d'Almeida, Amanda, Cook, Rachel, Danilov, Alexey, Dao, Kim-Hien T, Degnin, Michie, Dibb, James, Eide, Christopher A, English, Isabel, Hagler, Stuart, Harrelson, Heath, Henson, Rachel, Ho, Hibery, Joshi, Sunil K, Junio, Brian, Kaempf, Andy, Kosaka, Yoko, Laderas, Ted, Lawhead, Matt, Lee, Hyunjung, Leonard, Jessica T, Lin, Chenwei, Lind, Evan F, Liu, Selina Qiuying, Lo, Pierrette, Loriaux, Marc M, Luty, Samuel, Maxson, Julia E, Macey, Tara, Martinez, Jacqueline, Minnier, Jessica, Monteblanco, Andrea, Mori, Motomi, Morrow, Quinlan, Nelson, Dylan, Ramsdill, Justin, Rofelty, Angela, Rogers, Alexandra, Romine, Kyle A, Ryabinin, Peter, Saultz, Jennifer N, Sampson, David A, Savage, Samantha L, Schuff, Robert, Searles, Robert, Smith, Rebecca L, Spurgeon, Stephen E, Sweeney, Tyler, Swords, Ronan T, Thapa, Aashis, Thiel-Klare, Karina, Traer, Elie, Wagner, Jake, Wilmot, Beth, Wolf, Joelle, Wu, Guanming, Yates, Amy, Zhang, Haijiao, Cogle, Christopher R, Collins, Robert H, Deininger, Michael W, Hourigan, Christopher S, Jordan, Craig T, Lin, Tara L, Martinez, Micaela E, Pallapati, Rachel R, Pollyea, Daniel A, Pomicter, Anthony D, Watts, Justin M, Weir, Scott J, Druker, Brian J, McWeeney, Shannon K, Tyner, Jeffrey W
Format: Journal Article
Language:English
Published: United States 08.08.2022
Subjects:
Cell Differentiation
Cohort Studies
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - genetics
Receptors, Cell Surface - genetics
Transcriptome
targeted therapy
JEDI
leukemia stem cell
eigengene
LSC17
monocyte
MEGF12
hematologic malignancy
cell state
ISSN:1878-3686, 1878-3686
Online Access:Get more information
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Summary:Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.
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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2022.07.002