INTEGRATION OF GENOMIC AND EPIGENOMIC DATA REFINES THE REGULATORY MECHANISMS AND BIOLOGICAL SIGNIFICANCE OF CHRONIC LYMPHOCYTIC LEUKEMIA RISK LOCI
Author(s): ,
Renée Beekman
Affiliations:
IDIBAPS,Barcelona,Spain
,
Helen E. Speedy
Affiliations:
Institute of Cancer Research,London,United Kingdom
,
Vicente Chapaprieta
Affiliations:
Universitat de Barcelona,Barcelona,Spain
,
Giulia Orlando
Affiliations:
Institute of Cancer Research,London,United Kingdom
,
Philip J. Law
Affiliations:
Institute of Cancer Research,London,United Kingdom
,
David Martín-García
Affiliations:
IDIBAPS,Barcelona,Spain
,
Jesús Gutiérrez-Abril
Affiliations:
Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo,Oviedo,Spain
,
Daniel Catovsky
Affiliations:
Institute of Cancer Research,London,United Kingdom
,
Sílvia Beà
Affiliations:
IDIBAPS,Barcelona,Spain
,
Guillem Clot
Affiliations:
IDIBAPS,Barcelona,Spain
,
Montserrat Puiggros
Affiliations:
Barcelona Supercomputing Center (BSC),Barcelona,Spain
,
David Torrents
Affiliations:
Barcelona Supercomputing Center (BSC),Barcelona,Spain
,
Xose S. Puente
Affiliations:
Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo,Oviedo,Spain
,
James M. Allan
Affiliations:
Northern Institute for Cancer Research, Newcastle University,Newcastle upon Tyne,United Kingdom
,
Carlos López-Otín
Affiliations:
Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo,Oviedo,Spain
,
Elias Campo
Affiliations:
IDIBAPS,Barcelona,Spain
,
Richard S. Houlston
Affiliations:
Institute of Cancer Research,London,United Kingdom
José I. Martín-Subero
Affiliations:
IDIBAPS,Barcelona,Spain
EHA Library. Beekman R. Jun 14, 2019; 266155; PF355
Renée Beekman
Renée Beekman
Contributions
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Abstract

Abstract: PF355

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background

Chronic lymphocytic leukemia (CLL) has a strong genetic component, evidenced by an eight-fold increased risk to develop CLL in relatives of CLL patients. Genome-wide association studies (GWAS) have provided evidence for inherited predisposition to CLL, identifying 42 (non-HLA) genomic regions influencing CLL risk. However, efforts to define the mechanisms mediating the risk at these, largely non-coding, loci have been constrained by a lack of integrated genome-wide data in large CLL series.

Aims

We aimed to refine the gene regulatory mechanisms and biological significance of CLL risk loci.

Methods

We (i) analysed high-resolution chromatin state maps of primary CLL samples, (ii) integrated genetic, epigenetic and transcriptomic data in up to 452 primary CLL cases by quantitative trait loci (QTL) analysis, (iii) performed in silico transcription factor (TF) binding analysis using motifbreakR and (iv) studied the three-dimensional (3D) chromatin structure of normal B cells and CLL using promoter capture Hi-C data.

Results

Eighty-one percent of the 42 genomic risk loci were enriched for active regulatory elements (active promoters and enhancers) in CLL, suggesting a specific regulatory role for these loci in CLL pathogenesis. Additionally, at 18 risk loci we detected regulatory regions showing genotype dependent levels of genome activity (H3K27ac QTLs) and chromatin accessibility (ATAC-seq QTLs) in primary CLL cases. Moreover, within these QTLs, we defined 60 potential functional variants underlying genetic CLL predisposition.

Next, we focused on the underlying biological mechanisms through which genetic variants at CLL risk loci shape the regulatory genome by performing in silico TF binding analysis. We observed that genotypes associated with higher risk to develop CLL, among others, resulted in decreased binding affinity for B-cell related TFs and increased affinity for FOX, NFAT and TCF/LEF TF family members. Thus, our findings point towards a regulatory role for these TFs in CLL predisposition.

Thirdly, to infer the biological significance of CLL risk loci, we identified 36 genes that showed genotype dependent gene expression levels (eQTLs) in primary CLLs. These represent the potential target genes through which CLL risk loci mediate their effect and affected pathways known to be involved in CLL pathogenesis such as immune response, Wnt signalling and apoptosis. Interestingly, the eQTLs included new genes, such as TLE3, that have not been associated with CLL risk before. Lastly, we observed significant 3D chromatin interactions in CLL and normal B cells between the risk loci and 15 eQTL gene loci, highly suggestive for direct regulatory links between the risk loci and expression of these genes in relation to CLL predisposition. Importantly, these analyses showed that CLL risk loci not necessarily affect expression of the nearest gene but may mediate their effect in a more distant fashion, as shown for UBR5, due to long-range 3D chromatin interactions.

Conclusion

By (i) characterising the potential functional variants that influence the risk to develop CLL, (ii) defining the regulatory elements and the TFs that play a role in mediating the effect of genetic variation at the CLL risk loci and (iii) determining the downstream genotype-dependent effects on expression of both proximal and distant target genes at these regions, we offer improved insights into the functional and biological basis of CLL predisposition.

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research

Keyword(s): Chronic lymphocytic leukemia, Epigenetic, Gene regulation, Genetic polymorphism

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