Integrative Analysis of Drug Response and Clinical Outcome in Acute Myeloid Leukemia

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Cancer Cell. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4041405

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 new dataset, which has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort validation and identify new features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally impacting 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 new avenues for mechanistic exploration and drug development, and reveals new tools for predicting outcome in AML.

Our complete OHSU Beat AML cohort represents sample collection and characterization over a span of 10 years with integration of ex vivo drug sensitivity testing, curation of clinical annotations, and DNA- and RNA-sequencing to reveal mutational status and gene expression profiles. The data in Tyner et al (2018) consist of the first two waves of patient accrual and sample data from 11 academic medical centers (denoted as “Waves 1+2”). Here we provide additional longitudinal samples for Waves 1+2, updated clinical information, as well as new patient accrual, which represents the final two waves (“Waves 3+4”). Waves 3+4 is comprised of a total of 293 patient specimens from 279 patients (243 patients unique to Waves 3+4). In this manuscript we provide the harmonization of these data sets together, for a cumulative cohort of 942 specimens from 805 patients, which reflects a real-world cohort of AML cases, inclusive of de novo, transformed, and therapy-related AML as well as cases at the point of initial. Processed data is available at vizome.org and additional supplementary material accompanying the paper is available at https://biodev.github.io/BeatAML2/

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Data in the GDC

  • GDC Manifests
    • BEATAML1.0-COHORT WXS Tumor Only VCF Files Manifest (Controlled Access) - Download Manifest (227 files)
    • BEATAML1.0-COHORT Targeted Sequencing Tumor Only VCF Files Manifest (Controlled Access) - Download Manifest (171 files)

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