Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN.
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.
Haematologica. 2023 Feb 1;108(2):502-512. doi: 10.3324/haematol.2022.281157.
There is growing evidence for an inherited basis of susceptibility to childhood acute lymphoblastic leukemia. Genomewide association studies by us and others have identified non-coding acute lymphoblastic leukemia risk variants at the ARID5B gene locus, but the molecular mechanisms linking ARID5B to normal and malignant hematopoiesis remain largely unknown. Using a Vav1-driven transgenic mouse model, we characterized the role of Arid5b in hematopoiesis in vivo. Arid5b overexpression resulted in a dramatic reduction in the proportion of circulating B cells, immature, and mature Bcell fractions in the peripheral blood and the bone marrow, and also a decrease of follicular B cells in the spleen. There were significant defects in B-cell activation upon Arid5b overexpression in vitro with hyperactivation of B-cell receptor signaling at baseline. In addition, increased mitochondrial oxygen consumption rate of naïve or stimulated B cells of Arid5b-overexpressing mice was observed, compared to the rate of wild-type counterparts. Taken together, our results indicate that ARID5B may play an important role in B-cell development and function.
越来越多的证据表明，儿童急性淋巴细胞白血病易感性存在遗传基础。我们和其他研究人员进行的全基因组关联研究已经确定了 ARID5B 基因座上的非编码急性淋巴细胞白血病风险变异体，但 ARID5B 与正常和恶性造血之间的分子机制在很大程度上仍然未知。我们使用 Vav1 驱动的转基因小鼠模型，在体内描述了 Arid5b 在造血中的作用。Arid5b 的过表达导致循环 B 细胞、外周血和骨髓中未成熟和成熟 B 细胞的比例以及脾脏滤泡 B 细胞的比例显著降低。体外过表达 Arid5b 时，B 细胞激活存在明显缺陷，B 细胞受体信号在基线时过度激活。此外，与野生型相比，过表达 Arid5b 的幼稚或刺激 B 细胞的线粒体耗氧量增加。总之，我们的研究结果表明，ARID5B 可能在 B 细胞发育和功能中发挥重要作用。
