Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression

被引:129
作者
van Zelm, MC
van der Burg, M
de Ridder, D
Barendregt, BH
de Haas, EFE
Reinders, MJT
Lankester, AC
Révész, T
Staal, FJT
van Dongen, JJM
机构
[1] Univ Med Ctr Rotterdam, Mol Immunol Unit, Erasmus MC, Dept Immunol, NL-3015 GE Rotterdam, Netherlands
[2] Erasmus MC, Dept Pediat, Rotterdam, Netherlands
[3] Delft Univ Technol, Fac Elect Engn, Informat & Commun Theory Grp, Delft, Netherlands
[4] Leiden Univ, Med Ctr, Dept Pediat, Leiden, Netherlands
[5] Univ Utrecht, Med Ctr, Wilhelmina Childrens Hosp, Hematol Oncol Unit, Utrecht, Netherlands
关键词
D O I
10.4049/jimmunol.175.9.5912
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页码:5912 / 5922
页数:11
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