title: Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression.
abstract: 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.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Dick
authors.initials: D
authors.lastname: de Ridder
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Barendregt
authors.forename: Edwin F E
authors.initials: EF
authors.lastname: de Haas
authors.forename: Marcel J T
authors.initials: MJ
authors.lastname: Reinders
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.forename: Tom
authors.initials: T
authors.lastname: Révész
authors.forename: Frank J T
authors.initials: FJ
authors.lastname: Staal
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
mesh_terms: D000293:Adolescent; D016175:B-Lymphocyte Subsets / Q000378:metabolism*; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D020869:Gene Expression Profiling; D015322:Gene Rearrangement, B-Lymphocyte; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D005803:Genes, Immunoglobulin; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors