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Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia

Author

Listed:
  • Minjun Yang

    (Lund University)

  • Mattias Vesterlund

    (Science for Life Laboratory and Karolinska Institute, Clinical Proteomics Mass Spectrometry)

  • Ioannis Siavelis

    (Science for Life Laboratory and Karolinska Institute, Clinical Proteomics Mass Spectrometry)

  • Larissa H. Moura-Castro

    (Lund University)

  • Anders Castor

    (Skåne University Hospital, Lund University)

  • Thoas Fioretos

    (Lund University)

  • Rozbeh Jafari

    (Science for Life Laboratory and Karolinska Institute, Clinical Proteomics Mass Spectrometry)

  • Henrik Lilljebjörn

    (Lund University)

  • Duncan T. Odom

    (University of Cambridge, Li Ka Shing Centre
    Division of Signaling and Functional Genomics)

  • Linda Olsson

    (Lund University
    Office for Medical Services, Division of Laboratory Medicine)

  • Naveen Ravi

    (Lund University)

  • Eleanor L. Woodward

    (Lund University)

  • Louise Harewood

    (University of Cambridge, Li Ka Shing Centre
    Queen’s University Belfast)

  • Janne Lehtiö

    (Science for Life Laboratory and Karolinska Institute, Clinical Proteomics Mass Spectrometry)

  • Kajsa Paulsson

    (Lund University)

Abstract

Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects.

Suggested Citation

  • Minjun Yang & Mattias Vesterlund & Ioannis Siavelis & Larissa H. Moura-Castro & Anders Castor & Thoas Fioretos & Rozbeh Jafari & Henrik Lilljebjörn & Duncan T. Odom & Linda Olsson & Naveen Ravi & Elea, 2019. "Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09469-3
    DOI: 10.1038/s41467-019-09469-3
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    Cited by:

    1. Sophie A. Herbst & Mattias Vesterlund & Alexander J. Helmboldt & Rozbeh Jafari & Ioannis Siavelis & Matthias Stahl & Eva C. Schitter & Nora Liebers & Berit J. Brinkmann & Felix Czernilofsky & Tobias R, 2022. "Proteogenomics refines the molecular classification of chronic lymphocytic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Isabelle Rose Leo & Luay Aswad & Matthias Stahl & Elena Kunold & Frederik Post & Tom Erkers & Nona Struyf & Georgios Mermelekas & Rubin Narayan Joshi & Eva Gracia-Villacampa & Päivi Östling & Olli P. , 2022. "Integrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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