B cells generated by B‐1 development can progress to chronic lymphocytic leukemia

CD5+ B-cell origins and their predisposition to lymphoma are long-standing issues. chain DJ rearrangements on both chromosomes, but lack productively rearranged VDJs [6]. We called these Pro-B cells, to distinguish them from Pre-B cells that express heavy chain protein in their cytoplasm. When Pro-B cells were transferred into immunodeficient SCID mice that lack lymphoid populations, they generated mature B cells, but not other lymphoid cells and not a self-renewing precursor pool [6]. Pro-B cells with a phenotype similar to those in BM have been identified in fetal liver, and they possessed partial IgH rearrangements, similar to BM [7].We performed cell transfer experiments of these Pro-B cells into SCID mouse recipients, comparing the B cells generated from these committed B-cell precursors isolated from fetal and adult sources [7]. Flow cytometry analysis showed that the B cells generated by these Pro-B cells at two different stages in the animal's life are very different, with fetal precursors generating cells with a B1 Aspects of what we discuss below have also been previously reviewed as part of two presentations at a recent meeting devoted to B1 B cells [19,20]. Distinctions between fetal and adult B lymphopoiesisObvious questions raised by the Pro-B transfer experiments were, for example, how such a switch is mediated and what it consists of. We first attempted to analyze gene expression differences in fetal and adult Pro-B cells by performing global mRNA analysis [17]. Microarray analysis revealed a striking difference in the expression of terminal deoxynucleotidyltransferase (TdT), a gene that encodes the enzyme mediating nongermline nucleotide addition (N-addition) at the Ig heavy chain junctions [21]. A paucity of such N-addition limits CDR3 diversity, a critical component of Ig antigen recognition [22]. Furthermore, low TdT favors rearrangement of gene segments that share short regions of homology, limiting diversity [23]. Thus, differential expression of TdT is one reason for the difference between B-1 and B-2 development, since the IgH repertoires generated in their progeny will differ. However, this is not the complete explanation, since a TdT null mouse generated by gene targeting developed a mature pool of B cells that resembles B2/follicular B cells [24 and authors, unpublished].Development of B-cell pools with distinctive heavy chains could also occur by altered dependence on pre-BCR signaling [25]. BM B-cell development depends critically on assembly of a newly rearranged VDJ-μ heavy chain with preexisting B lineage specific proteins encoded by the genes λ5 and VpreB that together make up the surrogate light chain (SLC) [26,27]. Assembly of the IgH chain with SLC produces the pre-BCR, a complex that mediates a tonic signal indicating that a productive Ig heavy chain has been generated [28]. The pre-BCR also induces a number of changes in developing pre-B cells, including downregulation of the Rag proteins [29] and rapid proliferation of pre-B cells. An IgH rearrangement that is frequent in B...

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“…Aspects of what we discuss below have also been previously reviewed as part of two presentations at a recent meeting devoted to B1 B cells .…”

Section: A Word On Nomenclaturementioning

confidence: 99%

Perspectives on fetal derived CD5⁺ B1 B cells

Hardy

Hayakawa

2015

Eur J Immunol

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“…These findings suggest a role for IκBε in the generation or expansion of B1 progenitor pool. BCR signaling plays an instructive role in B1a cell lineage determination and maintenance 28,30,44,45 . In addition, recent studies showed that BCR signaling cooperates with TLR signaling in controlling expansion and activation of B1a B cells [46][47][48][49] .…”

Section: Discussionmentioning

confidence: 99%

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

et al. 2020

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Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.

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“…Our results may therefore suggest a crucial link between Ikaros loss and B1 cell-associated ALL. Finally, as CD5 ϩ B1 cells have been implicated in chronic lymphoid leukemia (CLL) (67), Ikaros may also act as a tumor suppressor in B1 cell-related CLL.…”

Section: Discussionmentioning

confidence: 99%

Ikaros Is a Negative Regulator of B1 Cell Development and Function

Macias-Garcia

Heizmann

Sellars

et al. 2016

Journal of Biological Chemistry

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B1 B cells secrete most of the circulating natural antibodies and are considered key effector cells of the innate immune response. However, B1 cell-associated antibodies often crossreact with self-antigens, which leads to autoimmunity, and B1 cells have been implicated in cancer. How B1 cell activity is regulated remains unclear. We show that the Ikaros transcription factor is a major negative regulator of B1 cell development and function. Using conditional knock-out mouse models to delete Ikaros at different locations, we show that Ikaros-deficient mice exhibit specific and significant increases in splenic and bone marrow B1 cell numbers, and that the B1 progenitor cell pool is increased ϳ10-fold in the bone marrow. Ikaros-null B1 cells resemble WT B1 cells at the molecular and cellular levels, but show a down-regulation of signaling components important for inhibiting proliferation and immunoglobulin production. Ikarosnull B1 cells hyper-react to TLR4 stimulation and secrete high amounts of IgM autoantibodies. These results indicate that Ikaros is required to limit B1 cell homeostasis in the adult.

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B cells generated by B‐1 development can progress to chronic lymphocytic leukemia

Cited by 17 publications

References 39 publications

Perspectives on fetal derived CD5⁺ B1 B cells

Perspectives on fetal derived CD5⁺ B1 B cells

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

Ikaros Is a Negative Regulator of B1 Cell Development and Function

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B cells generated by B‐1 development can progress to chronic lymphocytic leukemia

Cited by 17 publications

References 39 publications

Perspectives on fetal derived CD5+ B1 B cells

Perspectives on fetal derived CD5+ B1 B cells

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

Ikaros Is a Negative Regulator of B1 Cell Development and Function

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Perspectives on fetal derived CD5⁺ B1 B cells

Perspectives on fetal derived CD5⁺ B1 B cells