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Molecular mechanisms of ARID5B-mediated genetic susceptibility to acute lymphoblastic leukemia

ABSTRACT: Molecular mechanisms of ARID5B-mediated genetic susceptibility to acute lymphoblastic leukemia

PROVIDER: PRJNA802244 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17838446.fastq.gz	Fastqsanger.gz
	SRR17838446_1.fastq.gz	Fastqsanger.gz
	SRR17838446_2.fastq.gz	Fastqsanger.gz
	SRR17838447.fastq.gz	Fastqsanger.gz
	SRR17838447_1.fastq.gz	Fastqsanger.gz

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Molecular mechanisms of ARID5B-mediated genetic susceptibility to acute lymphoblastic leukemia

Project description:There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-ALL leukemogenesis remain largely unknown. In this study, by targeted sequencing in germline DNA of 5,008 children with ALL, we identified 31 common variants in ARID5B significantly associated with leukemia risk, all of which were non-coding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P=1.82×10-10) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The rs7090445 variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n=349,861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P=8.6×10-22 and 2.1×10-18, respectively). Taken together, our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus.

2022-08-11 | GSE195831 | GEO

Molecular Mechanisms of ARID5B-Mediated Genetic Susceptibility to Acute Lymphoblastic Leukemia.

Project description: Not available

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Germline genomic variations associated with childhood acute lymphoblastic leukemia

Project description:We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1x10-5) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P≤0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4x10-15, odds ratio[OR]=1.91; rs10994982, P=5.7x10-9, OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 x10-5, OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes. We used microarrays to detail the global program of gene expression in primary leukemic blasts cells from children diagnosed with acute lymphoblastic leukemia.

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Defining the interactome of ARID5B by AviTag protein pull-down coupled to quantitative mass spectrometry.

Project description:Among the strongest associations with pediatric B-cell acute lymphoblastic leukemia (B-ALL) are risk non-coding variants localized in the intron of ARID5B (AT-rich interaction domain 5B), a poorly characterized DNA-binding protein. In this study, we defined the interactome of ARID5B by LC-MS/MS and identified transcriptional repressors HDAC1, HDAC2, MIER1 and C16ORF87 as interactors. Structural predictions revealed that ARID5B and its interactors assemble into a repressor complex. We further validated and characterized the molecular function of the ARID5B repressor complex in B cells.

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Project description:We employed a combination of proteomics, genomics and transcriptomics to describe the molecular mechanisms of ARID5B. We identify that ARID5B interacts with MIER1, C16ORF87, HDAC1 and HDAC2 forming a repressor complex. The former localizes to active regions of the genome, tethering HDAC1 and HDAC2 to enhancers and promoters. Genes actively repressed by the ARID5B repressor complex are involved in B cell-specific signaling.

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Leukemia risk factor ARID5B Coordinates HDAC-Mediated Transcriptional Repression [RNA-Seq]

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