Acute myelogenous leukaemia (AML) is associated with risk factors that are largely unknown and with a heterogeneous response to treatment. Here, we provide a comprehensive quantitative understanding of AML proteomic heterogeneities and hallmarks by using the AML Proteome Atlas, a proteomics database that we have newly derived from MetaGalaxy analyses, for the proteomic profiling of 205 patients with AML and 111 leukaemia cell lines. The analysis of the dataset revealed 154 functional patterns based on common molecular pathways, 11 constellations of correlated functional patterns and 13 signatures that stratify the outcomes of patients. We find limited overlap between proteomics data and both cytogenetics and genetic mutations. Moreover, leukaemia cell lines show limited proteomic similarities with cells from patients with AML, suggesting that a deeper focus on patient-derived samples is needed to gain disease-relevant insights. The AML Proteome Atlas provides a knowledge base for proteomic patterns in AML, a guide to leukaemia cell line selection, and a broadly applicable computational approach for quantifying the heterogeneities of protein expression and proteomic hallmarks in AML.
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The datasets generated and analysed in the study are available on the AML Proteome Atlas: LeukemiaAtlas.org (direct dataset-download at https://www.leukemiaatlas.org/adultaml). Source data for the figures in this study are also provided in .xlsx and .csv formats in figshare at https://figshare.com/s/5ec75fb971747383c0be53 and are accessible directly from the AML Proteome Atlas (https://www.leukemiaatlas.org/adultaml).
Access to the entire code used in the MetaGalaxy analysis is listed in Supplementary Table 7. In particular, the Progeny Clustering code is available on the R repository at https://cran.r-project.org/web/packages/progenyClust/index.html, and the MetaGalaxy pipeline is available in a R Shiny portal at https://meta-galaxy-analysis.shinyapps.io/mpa_r/, with a corresponding tutorial and demo files (main.csv and pathway.csv) available in the supplement and online at the AML Proteome Atlas (https://www.leukemiaatlas.org/code).
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This research was funded in part by a translational research grant from the Leukemia and Lymphoma Society to S.M.K., NSF CAREER 1150645, NSF NCS 1533708 and NIH R01 GM106027 grants to A.A.Q., and a HHMI Med-into-Grad fellowship to C.W.H.
The authors declare no competing interests.
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Supplementary figures, tables and software tutorial.
Antibody nomenclature table.
Correlation between post-translational modifications and total protein expression levels.
Functional group memberships.
Constellation memberships for cell lines.
Functional pattern memberships for cell lines.
Demographic information of patients overall and in each signature (S1–S13).
Method implementation and parameter specification.
Stability scores from Progeny Clustering for co-clustering.
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Hu, C.W., Qiu, Y., Ligeralde, A. et al. A quantitative analysis of heterogeneities and hallmarks in acute myelogenous leukaemia. Nat Biomed Eng 3, 889–901 (2019) doi:10.1038/s41551-019-0387-2
Nature Biomedical Engineering (2019)
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