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

M Yang; M Vesterlund; I Siavelis; LH Moura-Castro; A Castor; T Fioretos; R Jafari; H Lilljebjörn; DT Odom; L Olsson; N Ravi; EL Woodward; L Harewood; K Paulsson

doi:10.1038/s41467-019-09469-3

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

M Yang, M Vesterlund, I Siavelis, LH Moura-Castro, A Castor, T Fioretos, R Jafari, H Lilljebjörn, DT Odom, L Olsson, N Ravi, EL Woodward, L Harewood, K Paulsson

School of Medicine, Dentistry and Biomedical Sciences

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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.

Original language	English
Article number	1519
Number of pages	15
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-09469-3
Publication status	Published - 03 Apr 2019

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Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia
Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Yang, M., Vesterlund, M., Siavelis, I., Moura-Castro, LH., Castor, A., Fioretos, T., Jafari, R., Lilljebjörn, H., Odom, DT., Olsson, L., Ravi, N., Woodward, EL., Harewood, L., & Paulsson, K. (2019). Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia. Nature Communications, 10, Article 1519. https://doi.org/10.1038/s41467-019-09469-3

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

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.",

author = "M Yang and M Vesterlund and I Siavelis and LH Moura-Castro and A Castor and T Fioretos and R Jafari and H Lilljebj{\"o}rn and DT Odom and L Olsson and N Ravi and EL Woodward and L Harewood and K Paulsson",

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Yang, M, Vesterlund, M, Siavelis, I, Moura-Castro, LH, Castor, A, Fioretos, T, Jafari, R, Lilljebjörn, H, Odom, DT, Olsson, L, Ravi, N, Woodward, EL, Harewood, L & Paulsson, K 2019, 'Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.', Nature Communications, vol. 10, 1519. https://doi.org/10.1038/s41467-019-09469-3

TY - JOUR

T1 - Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.

AU - Yang, M

AU - Vesterlund, M

AU - Siavelis, I

AU - Moura-Castro, LH

AU - Castor, A

AU - Fioretos, T

AU - Jafari, R

AU - Lilljebjörn, H

AU - Odom, DT

AU - Olsson, L

AU - Ravi, N

AU - Woodward, EL

AU - Harewood, L

AU - Paulsson, K

PY - 2019/4/3

Y1 - 2019/4/3

N2 - 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.

AB - 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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SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 1519

ER -

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

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