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. 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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Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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Declaration of interests C.E.T. receives research support from Notable Labs and serves as a scientific liaison for AstraZeneca. J.E.M. receives research funding from Gilead Pharmaceutical and serves on a scientific advisory board for Ionis Pharmaceuticals. M.W.D. serves on the advisory boards 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 Sellas. T.L.L. consults for Jazz Pharmaceuticals and receives research funding from Tolero, Gilead, Prescient, 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 advisory boards for Pfizer, Celyad, Agios, Celgene, AbbVie, Argenx, Takeda, and Servier. B.J.D. serves on the advisory boards for Aileron Therapeutics, Aptose, Blueprint Medicines, Cepheid, EnLiven Therapeutics, Gilead, GRAIL, Iterion Therapeutics, Nemucore Medical Innovations, the Novartis CML Molecular Monitoring Steering Committee, Recludix Pharma, the RUNX1 Research Program, ALLCRON Pharma, VB Therapeutics, Vincerx Pharma, and the Board of Directors for Amgen, and receives research funding from EnLiven and Recludix. B.J.D. is principal investigator or co-investigator on Novartis, BMS, and Pfizer clinical trials. His institution, OHSU, has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead, but he does not derive salary, nor does his laboratory receive funds, from these contracts. J.W.T. has received research support from Acerta, Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda, and Tolero and serves on the advisory board for Recludix Pharma. The authors certify that all compounds tested in this study were chosen without input from any of our industry partners. A subset of findings from this manuscript have been included in a pending patent application.