Repository logo
 

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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Vesterlund, Mattias  ORCID logo  https://orcid.org/0000-0001-9471-6592
Siavelis, Ioannis 
Moura-Castro, Larissa H 
Castor, Anders 

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.

Description

Keywords

Adolescent, Aneuploidy, CCCTC-Binding Factor, Cell Cycle Proteins, Child, Child, Preschool, Chromatin, Chromosomal Proteins, Non-Histone, Chromosome Aberrations, Core Binding Factor Alpha 2 Subunit, Female, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Genome, Human, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proteogenomics, Proteome, Proto-Oncogene Proteins c-ets, Repressor Proteins, Sequence Analysis, RNA, Transcription, Genetic, Cohesins, ETS Translocation Variant 6 Protein

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

10

Publisher

Springer Science and Business Media LLC
Sponsorship
European Research Council (615584)
Cancer Research UK (20412)
Cancer Research UK (22398)