Molecular Mechanisms of ARID5B-Mediated Genetic Susceptibility to Acute Lymphoblastic Leukemia.
Molecular Mechanisms of ARID5B-Mediated Genetic Susceptibility to Acute Lymphoblastic Leukemia.
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ARID5B 介导的急性淋巴细胞白血病遗传易感性的分子机制。
DOI：
10.1093/jnci/djac101
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Yang,
中科院分区：
文献类型：
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作者：
Zhao,Xujie;Qian,Maoxiang;Goodings,Charnise;Zhang,Yang;Yang,Wenjian;Wang,Ping;Xu,Beisi;Tian,Cheng;Pui,Ching-Hon;Hunger,StephenP;Raetz,ElizabethA;Devidas,Meenakshi;Relling,MaryV;Loh,MignonL;Savic,Daniel;Li,Chunliang;Yang,
背景越来越多的证据表明儿童急性淋巴细胞白血病（ALL）的易感性具有遗传基础。全基因组关联研究已经确定了 ARID5B 基因位点上的非编码 ALL 风险变异，但其确切的功能作用以及将 ARID5B 与 B 细胞 ALL 白血病发生联系起来的分子机制仍然很大程度上未知。 方法我们对 5008 名 ALL 儿童的种系 DNA 中的 ARID5B 进行了靶向测序。在附加模型下，使用来自 UK10K 队列的 3644 名患者作为非 ALL 对照，评估了变异与 ALL 易感性的关联。在 ALL 细胞中使用 dCas9-KRAB 介导的增强子干扰系统增强子筛选系统地鉴定了 ARID5B 中的顺式调节元件。通过信息预测 ARID5B 变体对转录因子结合的破坏，然后使用染色质免疫沉淀和免疫共沉淀进行确认。使用 UK Biobank 数据集检查了 ARID5B 变体与血液学特征的关联。所有统计检验都是双向的。结果我们在 ARID5B 中确定了 54 个常见变异，在统计上与白血病风险显着相关，所有这些变异都是非编码的。使用基于 CRISPR 的高通量增强子筛选发现了 ARID5Blocus 上的 Sixcis 调控元件。引人注目的是，最高的 ALL 风险变异 (rs7090445，P=5.57 × 10–45) 恰好位于最强的增强子元件内，该元件也与 ARID5B 启动子远端相连。变异等位基因破坏了 MEF2C 结合基序序列，导致 MEF2C 亲和力降低和局部染色体可及性降低。 MEF2C 可能通过与 RUNX1 的转录因子复合物影响 ALL 中 ARID5B 的表达。使用英国生物银行数据集（n = 349 861），我们发现rs7090445也与一般人群中的淋巴细胞百分比和计数相关（P分别为8.6 × 10–22和2.1 × 10–18）。结论我们的结果表明，ARID5B功能中的ALL风险变异通过调节顺式调控元件这个轨迹。
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 theARID5Bgene locus, but their exact functional effects and the molecular mechanism linkingARID5Bto B-cell ALL leukemogenesis remain largely unknown.MethodsWe performed targeted sequencing ofARID5Bin 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 inARID5Bwere systematically identified using dCas9-KRAB–mediated enhancer interference system enhancer screen in ALL cells. Disruption of transcription factor binding byARID5Bvariant was predicted informatically and then confirmed using chromatin immunoprecipitation and coimmunoprecipitation.ARID5Bvariant association with hematological traits was examined using UK Biobank dataset. All statistical tests were 2-sided.ResultsWe identified 54 common variants inARID5Bstatistically significantly associated with leukemia risk, all of which were noncoding. Sixcis-regulatory elements at theARID5Blocus 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 theARID5Bpromoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influencesARID5Bexpression 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 × 10–22and 2.1 × 10–18, respectively).ConclusionsOur results indicate that ALL risk variants inARID5Bfunction by modulatingcis-regulatory elements at this locus.