Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10p21.2
(2017) In Nature Communications 8.- Abstract
Despite high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL) being the most common subgroup of paediatric ALL, its aetiology remains unknown. Genome-wide association studies have demonstrated association at 10q21.2. Here, we sought to determine how this region influences HD-ALL risk. We impute genotypes across the locus, finding the single nucleotide polymorphism rs7090445 highly associated with HD-ALL (P=1.54 × 10'38), and residing in a predicted enhancer element. We show this region physically interacts with the transcription start site of ARID5B, that alleles of rs7090445 have differential enhancer activity and influence RUNX3 binding. RUNX3 knock-down reduces ARID5B expression and rs7090445 enhancer activity. Individuals... (More)
Despite high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL) being the most common subgroup of paediatric ALL, its aetiology remains unknown. Genome-wide association studies have demonstrated association at 10q21.2. Here, we sought to determine how this region influences HD-ALL risk. We impute genotypes across the locus, finding the single nucleotide polymorphism rs7090445 highly associated with HD-ALL (P=1.54 × 10'38), and residing in a predicted enhancer element. We show this region physically interacts with the transcription start site of ARID5B, that alleles of rs7090445 have differential enhancer activity and influence RUNX3 binding. RUNX3 knock-down reduces ARID5B expression and rs7090445 enhancer activity. Individuals carrying the rs7090445-C risk allele also have reduced ARID5B expression. Finally, the rs7090445-C risk allele is preferentially retained in HD-ALL blasts consistent with inherited genetic variation contributing to arrest of normal lymphocyte development, facilitating leukaemic clonal expansion. These data provide evidence for a biological mechanism underlying hereditary risk of HD-ALL at 10q21.2.
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- author
- Studd, James B. ; Vijayakrishnan, Jayaram ; Yang, Minjun LU ; Migliorini, Gabriele ; Paulsson, Kajsa LU and Houlston, Richard S.
- organization
- publishing date
- 2017-03-03
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Communications
- volume
- 8
- article number
- 14616
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:28256501
- wos:000395279800002
- scopus:85014578851
- ISSN
- 2041-1723
- DOI
- 10.1038/ncomms14616
- language
- English
- LU publication?
- yes
- id
- e77f9af1-641c-4369-9c48-bb4dad0ae268
- date added to LUP
- 2017-03-14 12:54:56
- date last changed
- 2025-01-07 09:34:49
@article{e77f9af1-641c-4369-9c48-bb4dad0ae268, abstract = {{<p>Despite high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL) being the most common subgroup of paediatric ALL, its aetiology remains unknown. Genome-wide association studies have demonstrated association at 10q21.2. Here, we sought to determine how this region influences HD-ALL risk. We impute genotypes across the locus, finding the single nucleotide polymorphism rs7090445 highly associated with HD-ALL (P=1.54 × 10'38), and residing in a predicted enhancer element. We show this region physically interacts with the transcription start site of ARID5B, that alleles of rs7090445 have differential enhancer activity and influence RUNX3 binding. RUNX3 knock-down reduces ARID5B expression and rs7090445 enhancer activity. Individuals carrying the rs7090445-C risk allele also have reduced ARID5B expression. Finally, the rs7090445-C risk allele is preferentially retained in HD-ALL blasts consistent with inherited genetic variation contributing to arrest of normal lymphocyte development, facilitating leukaemic clonal expansion. These data provide evidence for a biological mechanism underlying hereditary risk of HD-ALL at 10q21.2.</p>}}, author = {{Studd, James B. and Vijayakrishnan, Jayaram and Yang, Minjun and Migliorini, Gabriele and Paulsson, Kajsa and Houlston, Richard S.}}, issn = {{2041-1723}}, language = {{eng}}, month = {{03}}, publisher = {{Nature Publishing Group}}, series = {{Nature Communications}}, title = {{Genetic and regulatory mechanism of susceptibility to high-hyperdiploid acute lymphoblastic leukaemia at 10p21.2}}, url = {{http://dx.doi.org/10.1038/ncomms14616}}, doi = {{10.1038/ncomms14616}}, volume = {{8}}, year = {{2017}}, }