scholarly journals Localized Gene-Specific Induction of Accessibility to V(D)j Recombination Induced by E2a and Early B Cell Factor in Nonlymphoid Cells

2001 ◽  
Vol 194 (5) ◽  
pp. 645-656 ◽  
Author(s):  
Peter Goebel ◽  
Noel Janney ◽  
Joaquín R. Valenzuela ◽  
William J. Romanow ◽  
Cornelis Murre ◽  
...  
Keyword(s):  
B Cell ◽  
Ectopic Expression ◽  
Gene Families ◽  
Individual Gene ◽  
Germline Transcription ◽  
Specific Induction ◽  
Recombination Activating Gene ◽  
Direct Targeting ◽  
B Cell Precursors ◽  
Early B Cell Factor

Accessibility of immunoglobulin (Ig) gene segments to V(D)J recombination is highly regulated and is normally only achieved in B cell precursors. We previously showed that ectopic expression of E2A or early B cell factor (EBF) with recombination activating gene (RAG) induces rearrangement of IgH and IgL genes in nonlymphoid cells. VκI genes throughout the locus were induced to rearrange after transfection with E2A, suggesting that the entire Vκ locus was accessible. However, here we show that Ig loci are not opened globally but that recombination is localized. Gene families are interspersed in the DH, Vκ, and Vλ loci, and we show that certain families and individual genes undergo high levels of recombination after ectopic expression of E2A or EBF, while other families within the same locus are not induced to rearrange. Furthermore, in some families, induction of germline transcription correlates with the level of induced recombination, while in others there is no correlation, suggesting that recombination is not simply initiated by induction of germline transcription. The induced repertoire seen at 24 hours does not change significantly over time indicating the absence of many secondary rearrangements and also suggesting a direct targeting mechanism. We propose that accessibility occurs in a local manner, and that binding sites for factors facilitating accessibility are therefore likely to be associated with individual gene segments.

scholarly journals Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

2017 ◽  
Vol 114 (20) ◽  
pp. E4030-E4039 ◽  
Author(s):  
Omer Schwartzman ◽  
Angela Maria Savino ◽  
Michael Gombert ◽  
Chiara Palmi ◽  
Gunnar Cario ◽  
...  
Keyword(s):  
Down Syndrome ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Genomic Analysis ◽  
Loss Of Function ◽  
Genomic Databases ◽  
Ras Pathway ◽  
Signaling Inhibitors ◽  
Direct Targeting ◽  
B Cell Precursors

Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic “Philadelphia-like” ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are “relapse driving.” We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2pos DS-ALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2pos, Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT “hypersignaling” may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.

scholarly journals The B29 (Immunoglobulin β-Chain) Gene Is a Genetic Target for Early B-Cell Factor

1999 ◽  
Vol 19 (1) ◽  
pp. 392-401 ◽  
Author(s):  
Peter Åkerblad ◽  
Maria Rosberg ◽  
Tomas Leanderson ◽  
Mikael Sigvardsson
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
Chain Gene ◽  
Early B Cell Factor

ABSTRACT Early B-cell factor (EBF) is a transcription factor suggested as essential for early B-lymphocyte development by findings in mice where the coding gene has been inactivated by homologous disruption. This makes the identification of genetic targets for this transcription factor pertinent for the understanding of early B-cell development. The lack of B29 transcripts, coding for the β subunit of the B-cell receptor complex, in pro-B cells from EBF-deficient mice suggested that B29 might be a genetic target for EBF. We here present data suggesting that EBF interacts with three independent sites within the mouse B29 promoter. Furthermore, ectopic expression of EBF in HeLa cells activated a B29promoter-controlled reporter construct 13-fold and induced a low level of expression from the endogenous B29 gene. Finally, mutations in the EBF binding sites diminished B29 promoter activity in pre-B cells while the same mutations did not have as striking an effect on the promoter function in B-cell lines of later differentiation stages. These data suggest that the B29gene is a genetic target for EBF in early B-cell development.

scholarly journals Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a

2015 ◽  
Vol 212 (4) ◽  
pp. 569-580 ◽  
Author(s):  
Yan Zhou ◽  
Yue-Sheng Li ◽  
Srinivasa Rao Bandi ◽  
Lingjuan Tang ◽  
Susan A. Shinton ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Fetal Liver ◽  
Ectopic Expression ◽  
B Cell Antigen Receptor ◽  
B Lymphopoiesis ◽  
Bcr Signaling ◽  
B Cell Precursors ◽  
Adult Bone

Mouse B cell precursors from fetal liver and adult bone marrow (BM) generate distinctive B cell progeny when transplanted into immunodeficient recipients, supporting a two-pathway model for B lymphopoiesis, fetal “B-1” and adult “B-2.” Recently, Lin28b was shown to be important for the switch between fetal and adult pathways; however, neither the mechanism of Lin28b action nor the importance of B cell antigen receptor (BCR) signaling in this process was addressed. Here, we report key advances in our understanding of the regulation of B-1/B-2 development. First, modulation of Let-7 in fetal pro-B cells is sufficient to alter fetal B-1 development to produce B cells resembling the progeny of adult B-2 development. Second, intact BCR signaling is required for the generation of B1a B cells from Lin28b-transduced BM progenitors, supporting a requirement for ligand-dependent selection, as is the case for normal B1a B cells. Third, the VH repertoire of Lin28b-induced BM B1a B cells differs from that of normal B1a, suggesting persisting differences from fetal progenitors. Finally, we identify the Arid3a transcription factor as a key target of Let-7, whose ectopic expression is sufficient to induce B-1 development in adult pro-B cells and whose silencing by knockdown blocks B-1 development in fetal pro-B cells.

scholarly journals Induction of Early B Cell Factor (EBF) and Multiple B Lineage Genes by the Basic Helix-Loop-Helix Transcription Factor E12

1998 ◽  
Vol 188 (4) ◽  
pp. 699-713 ◽  
Author(s):  
Barbara L. Kee ◽  
Cornelis Murre
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
B Lymphocytes ◽  
Ectopic Expression ◽  
Helix Loop Helix ◽  
Rag 1 ◽  
B Lineage ◽  
Early B Cell Factor ◽  
Mitogen Activation

The transcription factors encoded by the E2A and early B cell factor (EBF) genes are required for the proper development of B lymphocytes. However, the absence of B lineage cells in E2A- and EBF-deficient mice has made it difficult to determine the function or relationship between these proteins. We report the identification of a novel model system in which the role of E2A and EBF in the regulation of multiple B lineage traits can be studied. We found that the conversion of 70Z/3 pre-B lymphocytes to cells with a macrophage-like phenotype is associated with the loss of E2A and EBF. Moreover, we show that ectopic expression of the E2A protein E12 in this macrophage line results in the induction of many B lineage genes, including EBF, IL7Rα, λ5, and Rag-1, and the ability to induce κ light chain in response to mitogen. Activation of EBF may be one of the critical functions of E12 in regulating the B lineage phenotype since expression of EBF alone leads to the activation of a subset of E12-inducible traits. Our data demonstrate that, in the context of this macrophage line, E12 induces expression of EBF and together these transcription factors coordinately regulate numerous B lineage–associated genes.

Dynamic Expression and New Functions of Early B Cell Factor 2 in Cerebellar Development

2019 ◽  
Vol 18 (6) ◽  
pp. 999-1010
Author(s):  
Aurora Badaloni ◽  
Filippo Casoni ◽  
Laura Croci ◽  
Francesca Chiara ◽  
Antonella Bizzoca ◽  
...  
Keyword(s):  
B Cell ◽  
Cerebellar Development ◽  
Dynamic Expression ◽  
Early B Cell Factor

scholarly journals Novel B-cell precursors blocked at the stage of DJH recombination.

1988 ◽  
Vol 8 (12) ◽  
pp. 5216-5223 ◽  
Author(s):  
L Ramakrishnan ◽  
N Rosenberg
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Leukemia Virus ◽  
Variable Region ◽  
Immunoglobulin Gene ◽  
Recombination System ◽  
Rearrangement Process ◽  
B Cell Precursors ◽  
Enzymatic Machinery

Abelson murine leukemia virus-transformed cells have provided the principal model for study of the early events in immunoglobulin gene rearrangements. In this communication, we describe a new type of Abelson virus-transformed pre-B-cell line that is arrested at the DJH stage of the recombination process. These cells differ from other pre-B transformants with respect to two properties associated with the immunoglobulin rearrangement process. First, in contrast to cell lines undergoing VH-to-DJH joining in vitro, none of these cell lines contained detectable levels of RNAs transcribed from their unrearranged VH genes. Second, only some of the cell lines recombined exogenous heptamer-nonamer sequences, indicating that many of them have lost at least a portion of the enzymatic machinery that mediates recombination. The correlation between the absence of unrearranged VH RNAs and the inability to rearrange endogenous immunoglobulin gene segments suggests that VH gene transcription is required both to maintain an active recombination system and for the final step in variable-region formation.

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