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

Yang, Minjun LU ; Vesterlund, Mattias ; Siavelis, Ioannis ; Moura-Castro, Larissa H. LU ; Castor, Anders LU ; Fioretos, Thoas LU ; Jafari, Rozbeh ; Lilljebjörn, Henrik LU ; Odom, Duncan T. and Olsson, Linda LU , et al. (2019) In Nature Communications 10(1).
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... (More)

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.

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Nature Communications
volume
10
issue
1
article number
1519
publisher
Nature Publishing Group
external identifiers
  • pmid:30944321
  • scopus:85063941879
ISSN
2041-1723
DOI
10.1038/s41467-019-09469-3
language
English
LU publication?
yes
id
23488743-b6a5-438e-8d1f-7c71d3f89d57
date added to LUP
2019-04-24 09:09:39
date last changed
2020-02-12 09:59:50
@article{23488743-b6a5-438e-8d1f-7c71d3f89d57,
  abstract     = {<p>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 &gt;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.</p>},
  author       = {Yang, Minjun and Vesterlund, Mattias and Siavelis, Ioannis and Moura-Castro, Larissa H. and Castor, Anders and Fioretos, Thoas and Jafari, Rozbeh and Lilljebjörn, Henrik and Odom, Duncan T. and Olsson, Linda and Ravi, Naveen and Woodward, Eleanor L. and Harewood, Louise and Lehtiö, Janne and Paulsson, Kajsa},
  issn         = {2041-1723},
  language     = {eng},
  month        = {04},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia},
  url          = {http://dx.doi.org/10.1038/s41467-019-09469-3},
  doi          = {10.1038/s41467-019-09469-3},
  volume       = {10},
  year         = {2019},
}