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.
Highlights
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
The relative downregulation of pathways related to chromatin organization, modifications and structure may be related to a higher proliferative capacity of ETV6/RUNX1-positive cases, but could be associated with epigenetic events in high hyperdiploid ALL, in particular in light of the changes in chromatin organization that we found by high-resolution chromosome conformation capture (Hi-C) in this subtype
Comparing the topologically associating domain (TAD) boundaries of our samples with the high resolution Hi-C dataset from the human lymphoblastoid cell line GM12878 31 showed that approximately 70% of the TAD boundaries we found were present in GM12878, indicating that the overall TAD structure was intact in the leukemia samples (Fig. 5, Supplementary Data 13)
Summary
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. In spite of the huge efforts that have gone into understanding the impact of somatic genetic events in cancer, the effects of aneuploidy in tumorigenesis remain poorly understood. Half of cases harbor mutations in the RTK–RAS pathway, primarily KRAS, and 20% have mutations in histone modifiers such as CREBBP, in addition to microdeletions of various genes involved in B-cell differentiation/cell cycle control[3,4] These additional aberrations are seen only in a subset of the cases, are sometimes gained or lost at relapse, and, when occurring, are frequently subclonal, whereas the aneuploidy is uniformly present[3,4]. Besides demonstrating that the characteristic extra chromosomes have an impact on the transcriptome and proteome, we present data suggesting that hyperdiploid leukemia cases harbor aberrant chromatin organization that causes genome-wide transcriptional dysregulation. Our data give insight into the leukemogenesis of this common and clinically important pediatric leukemia
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
