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

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, Eleanor L. Woodward, Louise Harewood, Janne Lehtiö () and Kajsa Paulsson ()
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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
Linda Olsson: Lund University
Naveen Ravi: Lund University
Eleanor L. Woodward: Lund University
Louise Harewood: University of Cambridge, Li Ka Shing Centre
Janne Lehtiö: Science for Life Laboratory and Karolinska Institute, Clinical Proteomics Mass Spectrometry
Kajsa Paulsson: Lund University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09469-3

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