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

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, Lehtiö J, Paulsson K

Nat Commun 10 (1) 1519 [2019-04-03; online 2019-04-03]

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.

Bioinformatics Support for Computational Resources [Service]

Clinical Genomics Lund [Service]

Global Proteomics and Proteogenomics [Technology development]

PubMed 30944321

DOI 10.1038/s41467-019-09469-3

Crossref 10.1038/s41467-019-09469-3

pii: 10.1038/s41467-019-09469-3
pmc: PMC6447538