Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
J Immunol. 2013 Mar 1;190(5):2080-9. doi: 10.4049/jimmunol.1202736. Epub 2013 Jan 23.
The development of mature B cells from hematopoietic stem cells is a strictly orchestrated process involving multiple regulatory genes. The transcription factor Sox4 is required for this process, but its role has not been systematically studied, and the underlying mechanisms remain unknown. To determine when and how Sox4 functions in the stepwise process of B cell development, we used mice harboring conditional null alleles for Sox4 and a Cre transgene. Sox4 deletion in hematopoietic stem cells almost entirely eliminated pro-B cells in both fetal livers and adult bone marrow, resulting in a severe deficiency in later stage B cells, including circulating mature B cells. Sox4-deficient pro-B cells, particularly those expressing the stem cell factor receptor c-Kit, readily underwent apoptosis, and even more so when c-Kit activity was inhibited by imatinib. C-Kit-expressing pro-B cells showed decreased activation of the c-Kit downstream protein Src upon Sox4 deletion. Likewise, the level of the anti-apoptotic Bcl2 protein was decreased in residual pro-B cells, and its restoration using a Bcl2 transgene allowed not only partial rescue of pro-B cell survival but also B cell maturation in the absence of Sox4. Our findings indicate that Sox4 is required for the survival of pro-B cells and may functionally interact with c-Kit and Bcl2.
成熟 B 细胞由造血干细胞发育而来，这是一个严格协调的过程，涉及多个调控基因。转录因子 Sox4 是这个过程所必需的，但它的作用尚未被系统研究，其潜在机制仍不清楚。为了确定 Sox4 在 B 细胞发育的逐步过程中何时以及如何发挥作用，我们使用了携带 Sox4 条件性缺失等位基因和 Cre 转基因的小鼠。造血干细胞中 Sox4 的缺失几乎完全消除了胎肝和成年骨髓中的前 B 细胞，导致后期 B 细胞（包括循环成熟 B 细胞）严重缺乏。Sox4 缺失的前 B 细胞，特别是那些表达干细胞因子受体 c-Kit 的前 B 细胞，很容易发生细胞凋亡，而当 c-Kit 活性被伊马替尼抑制时，凋亡更为严重。Sox4 缺失后，c-Kit 表达的前 B 细胞中 c-Kit 下游蛋白 Src 的激活减少。同样，残余前 B 细胞中抗凋亡蛋白 Bcl2 的水平降低，使用 Bcl2 转基因进行恢复不仅允许前 B 细胞存活得到部分挽救，而且在没有 Sox4 的情况下也允许 B 细胞成熟。我们的研究结果表明，Sox4 是前 B 细胞存活所必需的，并且可能与 c-Kit 和 Bcl2 具有功能相互作用。
