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Subtype-specific regulatory network rewiring in acute myeloid leukemia

Nature Genetics volume 51, pages 151–162 (2019)Cite this article

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Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype–specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

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Fig. 1: Different types of AML adopt unique transcriptome and chromatin landscapes.
Fig. 2: AML-specifically active cis-regulatory elements cluster into common and unique chromatin landscapes.
Fig. 3: AML-specifically active cis-regulatory elements display AML type–specific transcription factor occupancy patterns.
Fig. 4: AML cells show occupied motif patterns unrelated to normal progenitor cells.
Fig. 5: Capture HiC shows differences in locus-specific cis-regulatory interactions between different types of AML and normal cells.
Fig. 6: Identification of transcription factor networks driving expression of AML type–specific upregulated transcription factor genes.
Fig. 7: Identification of AML type–specific transcription factors required for maintaining leukemic growth and colony-forming ability.

Data availability

Raw data have been deposited at GEO under accession number GSE108316. Processed data are available from our data server (http://bioinformatics-bham.co.uk/tfinaml/).

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Acknowledgements

This research was funded by a program grant from Bloodwise (15001) to C.B. and P.N.C., as well as studentship awards from Cancer Research UK and Bloodwise to A.Pickin and N.G., respectively, a Kay Kendall Clinical Training Fellowship for J.L. and a MRC/Leuka Clinical Training Fellowship for S.P.

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Author notes

  1. These authors contributed equally: S. A. Assi, M. R. Imperato, D. J. L. Coleman.

Authors and Affiliations

  1. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK

    Salam A. Assi, Maria Rosaria Imperato, Daniel J. L. Coleman, Anna Pickin, Sandeep Potluri, Anetta Ptasinska, Paulynn Suyin Chin, Pierre Cauchy, Joaquin Zacarias-Cabeza, L. Niall Gilding, Andrew Beggs, Justin C. Loke, Manoj Raghavan, Peter N. Cockerill & Constanze Bonifer

  2. Northern Institute for Cancer Research, University of Newcastle, Newcastle, UK

    Helen Blair & Olaf Heidenreich

  3. Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK

    Sally R. James

  4. West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Birmingham, UK

    Sam Clokie & Michael J. Griffiths

  5. CMT Laboratory NHS Blood & Transplant, Edgbaston, Birmingham, UK

    Phil Jenkin & Ash Uddin

  6. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Ruud Delwel

  7. Oncode Institute, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    Ruud Delwel

  8. Haematological Malignancy Diagnostic Service, St. James’s University Hospital, Leeds, UK

    Stephen J. Richards

  9. Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK

    Manoj Raghavan

  10. Princess Maxima Centrum for Pediatric Oncology, Utrecht, The Netherlands

    Olaf Heidenreich

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  1. Salam A. Assi
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Contributions

M.R.I., D.J.L.C., S.P., A.Ptasinska, H.B., A.Pickin, L.N.G., J.C.L., P.S.C., J.Z.-C. and S.R.J. performed experiments and generated data; R.D., M.R., S.J.R., M.J.G., P.J. and A.U. provided subject samples; S.C., A.B. and P.N.C. conducted mutation analysis; S.A.A. and P.C. analyzed data; O.H. supervised transplantation experiments and helped edit the manuscript; C.B. and P.N.C. conceived and directed the study and C.B. wrote the manuscript.

Corresponding authors

Correspondence to Peter N. Cockerill or Constanze Bonifer.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, Supplementary Tables 1–3 and Supplementary Note

Reporting Summary

Supplementary Data 1

Summary of all AML mutation data

Supplementary Data 2

Up- and downregulated genes associated with mutation groups

Supplementary Data 3

Number of RNA-seq differentially expressed genes for Fig. SN1 and Supplementary Fig. 4c

Supplementary Data 4

AML subtype-specific transcription factor gene expression

Supplementary Data 5

Supplementary Data 6

Gene lists and GO terms for Supplementary Figs. 5 and 7

Supplementary Data 7

Statistical data fmr validations

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Assi, S.A., Imperato, M.R., Coleman, D.J.L. et al. Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nat Genet 51, 151–162 (2019). https://doi.org/10.1038/s41588-018-0270-1

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