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 DH-JH rearrangements, which are completed with VH-DJH 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.

Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement

“…40 This would fit with the immaturity of infant ALL as RAG1/2 levels during normal B-cell development are highest during DH-JH and VH-DH-JH gene rearrangements. 43 It has previously been shown that CD34 positivity was more common in MLL-AF4-positive ALL cases compared to E2A-PBX1-positive ALL cases, also supporting the immaturity of the malignant MLL-AF4-positive cell. 20 Furthermore, there is convincing evidence for prenatal development of the MLL-AF4 fusion gene as the main initiating event in t(4;11) positive infant leukemias.…”

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

“…One third of the intronic DMRs (3,341) were located within 150 base pairs of the 5 0 or 3 0 splice sites and could potentially alter appropriate splicing in ALL. To investigate whether the intergenic and intronic DMRs coincided with the location of regulatory enhancer elements, the sites for intergenic and intronic DMRs were overlaid with ENCODE ChIP-seq data for enhancer related histone marks (H3K4me1 and H3K27ac) in the GM12878 lymphoblastoid cell line.…”

“…1 The development and differentiation of B-cells comprises numerous stages and is a highly synchronized and controlled process governed by stage-specific gene expression. 2,3 Any deviation from normal stage-specific gene expression could lead to disease conditions including ALL. The general known mechanisms underlying the induction of ALL include chromosomal translocation, hyperdiploidy, and aberrant expression of proto-oncogenes.…”

Acute lymphoblastic leukemia with t(4;11) in children 1 year and older: The ‘big sister’ of the infant disease?

“…On the other hand, if this attemptincluding additional rescue mechanisms -fails to produce a functional Igm protein, the cell will undergo apoptotic cell death unless it carries a mutation that interferes with the execution of that decision. 14,15 This order of recombination seems to be maintained in B-cell precursor (BCP) ALL 16 . The frequency and types of rearrangements have been related to the genotype of BCP leukemias in the past and they also appear to be influenced by the target cell of the chromosomal translocation and the effects of the resulting fusion gene (TEL-AML1, E2A-PBX1).…”