Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression
Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression
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DOI：
10.4049/jimmunol.175.9.5912
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发表时间：
2005-11-01
影响因子：
4.4
通讯作者：
van Dongen, JJM
中科院分区：
文献类型：
--
作者：
van Zelm, MC;van der Burg, M;van Dongen, JJM
特异性转录因子在Ig基因重排的启动和调控中的作用已经在小鼠模型中得到了广泛的研究，但关于正常人类前体B细胞分化的数据有限。我们纯化了5个人前体B细胞亚群，并评估和量化了它们的IGH、IGK和IGL基因重排模式和基因表达谱。前b细胞已经大量启动D-H-J(H)重排，而前b - i细胞则通过V-H-DJ(H)重排完成。选择大循环前b - ii细胞进行帧内IGH基因重排。第一个IGK/IGL基因重排始于前B- i细胞，但其频率在小的前B- ii细胞中大大增加，并且在未成熟的B细胞中发现了框内选择。RAG1和RAG2基因的转录本以及早期定义的转录因子，如E2A、早期B细胞因子、E2-2、PAX5和IRF4，在Ig基因重排阶段特异性上调。基于Ig基因重排状态和连续前体B细胞亚群的基因表达谱，我们确定了16个参与Ig基因重排起始和/或调控的候选基因。这些分析为早期人类前体B细胞分化步骤提供了新的见解，并为前体B急性淋巴细胞白血病的癌性转化和原发性Ab缺陷的B细胞分化阻断研究提供了一个极好的模板。
The role of specific transcription factors in the initiation and regulation of Ig gene rearrangements has been studied extensively in mouse models, but data on normal human precursor B cell differentiation are limited. We purified five human precursor B cell subsets and assessed and quantified their IGH, IGK, and IGL gene rearrangement patterns and gene expression profiles. Pro-B cells already massively initiate D-H-J(H) rearrangements, which are completed with V-H-DJ(H) rearrangements in pre-B-I cells. Large cycling pre-B-II cells are selected for in-frame IGH gene rearrangements. The first IGK/IGL gene rearrangements were initiated in pre-B-I cells, but their frequency increased enormously in small pre-B-II cells, and in-frame selection was found in immature B cells. Transcripts of the RAG1 and RAG2 genes and earlier defined transcription factors, such as E2A, early B cell factor, E2-2, PAX5, and IRF4, were specifically up-regulated at stages undergoing Ig gene rearrangements. Based on the combined Ig gene rearrangement status and gene expression profiles of consecutive precursor B cell subsets, we identified 16 candidate genes involved in initiation and/or regulation of Ig gene rearrangements. These analyses provide new insights into early human precursor B cell differentiation steps and represent an excellent template for studies on oncogenic transformation in precursor B acute lymphoblastic leukemia and B cell differentiation blocks in primary Ab deficiencies.