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The Role of ARID5B in Acute Lymphoblastic Leukemia and Beyond.

ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children with distinct characteristics among different subtypes. Although the etiology of ALL has not been fully unveiled, initiation of ALL has been demonstrated to partly depend on genetic factors. As indicated by several genome wide association studies (GWASs) and candidate gene analyses, ARID5B, a member of AT-rich interactive domain (ARID) protein family, is associated with the occurrence and prognosis of ALL. However, the mechanisms by which ARID5B genotype impact on the susceptibility and treatment outcome remain vague. In this review, we outline developments in the understanding of ARID5B in the susceptibility of ALL and its therapeutic perspectives, and summarize the underlying mechanisms based on the limited functional studies, hoping to illustrate the possible mechanisms of ARID5B impact and highlight the potential treatment regimens.

SUBMITTER: Wang P

PROVIDER: S-EPMC7303299 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Role of ARID5B in Acute Lymphoblastic Leukemia and Beyond.

Wang Peiqi P Deng Yun Y Yan Xinyu X Zhu Jianhui J Yin Yuanyuan Y Shu Yang Y Bai Ding D Zhang Shouyue S Xu Heng H Lu Xiaoxi X

Frontiers in genetics 20200612

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children with distinct characteristics among different subtypes. Although the etiology of ALL has not been fully unveiled, initiation of ALL has been demonstrated to partly depend on genetic factors. As indicated by several genome wide association studies (GWASs) and candidate gene analyses, ARID5B, a member of AT-rich interactive domain (ARID) protein family, is associated with the occurrence and prognosis of ALL. However, the ...[more]

PMID: 32595701

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Project description:BackgroundThere 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-cell ALL leukemogenesis remain largely unknown.MethodsWe performed targeted sequencing of ARID5B in germline DNA of 5008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3644 patients from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using dCas9-KRAB-mediated enhancer interference system enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and coimmunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests were 2-sided.ResultsWe identified 54 common variants in ARID5B statistically significantly associated with leukemia risk, all of which were noncoding. 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 = 5.57 × 10-45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The 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).ConclusionsOur results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus.

Project description:Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95%CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95%CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95%CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms.

Dataset Information

The Role of ARID5B in Acute Lymphoblastic Leukemia and Beyond.

Publications

The Role of ARID5B in Acute Lymphoblastic Leukemia and Beyond.

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