There is growing evidence for an inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies by us and others have identified non-coding ALL 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 B-cell fractions in the peripheral blood and the bone marrow, and also decrease of follicular B cells in the spleen. There were significant defects in Bcell activation upon Arid5b overexpression in vitro with hyperactivation of the B-cell receptor signaling at baseline. In addition, increased mitochondrial oxygen consumption rate of naïve or stimulated B cells of Arid5bOE mice was observed, compared to wildtype counterparts. Taken together, our results indicate that ARID5B may play important role in B-cell development and function.
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