Pax5 – a Critical Inhibitor of Plasma Cell Fate

Nera, Kalle‐Pekka; Lassila, O.

doi:10.1111/j.1365-3083.2006.01809.x

Cited by 27 publications

(30 citation statements)

References 100 publications

(292 reference statements)

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“…14 Thus, repression of PAX5 is important for inhibiting B-lymphocyte functions and is required for PC functions. 15,16 Moreover, recent studies demonstrate the oncogenic role of BSAP by mutations or alterations in the expression of PAX5 gene. [17][18][19][20][21] Murine B-lymphocyte-induced maturation protein-1 (BLIMP1), or its human homologue positive regulatory domain I binding factor 1 (PRDI-BF1), is a transcription factor that has been demonstrated to act as a master regulator required 10 and sufficient 22 for the generation and for the prolonged maintenance of PCs.…”

Section: Introductionmentioning

confidence: 99%

“…The discrepancy in results observed between these studies 13,39 has been considered to be due to the PAX5 deficiency being originated in different maturational states of B cells. 15 However, the possibility of a difference in the regulation of B-cell activation between species cannot be excluded. In this context, the comparison of the BSAP-binding sequence of the PRDM1 promoter between human (or mouse) and chicken revealed a significantly reduced matching of the chicken sequences (CAGC-CCTCCAGTGTCTCGGAAAGGCA) with respect to the BSAPbinding consensus sequence (NCNNNRNKCANNGNWGN-RKRGCSRSN).…”

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confidence: 99%

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Human BSAP and BLIMP1 conform an autoregulatory feedback loop

Mora-López

Reales

Brieva

et al. 2007

Blood

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B-lymphocyte-induced maturation protein-1 (BLIMP1), encoded by the PRDM1 gene, is a transcriptional repressor considered a master regulator that is required and sufficient for plasma cell (PC) differentiation. BLIMP1 represses the PAX5 gene, coding for the B-cell lineage-specific activator protein (BSAP), which is required for B-cell identity and survival. Mutations in PAX5 gene as well as in PRDM1 gene have been recently implicated in lymphomas. In the present study, sequence analysis of PRDM1 gene revealed a binding site for BSAP transcription factor. By analyzing different human cell lines, we have found that a specific nuclear factor for B-cell lines binds to a site on the PRDM1 promoter. Electrophoretic mobility shift assays identified this factor as BSAP, and chromatin immunoprecipitation assays confirmed its binding in vivo to the human PRDM1 promoter. Moreover, by ectopically expressing BSAP, and using a IntroductionIn multicellular organisms, cell development and cell differentiation into many cell types is under the control of transcriptional factors. In the vertebrate immune system, the B-lymphocyte developmental pathway represents a model for the analysis of genetic networks, which orchestrate cell fate specification and commitment. Plasma cell (PC) differentiation from B lymphocyte depends on the switch-on/-off balance between transcription factors. 1,2 In this context, BSAP is a critical transcription factor required to establish and maintain B-cell lineage identity until the PC stage. [3][4][5] BSAP is a bifunctional transcription factor that can, depending on the gene context, either activate transcription of genes involved in maintaining B-cell identity including CD19, 6 Ig␣, BLNK, and CIITA 4 or repress transcription of PC-associated gene commitment such as J chain, IgH, IgL, and XBP1. [7][8][9][10] In the absence of PAX5, the gene coding for BSAP, progenitor B cells acquire the ability to differentiate into multiple hematopoietic lineages both in vitro and in vivo. [11][12][13] On the other hand, overexpression of PAX5 in the late stage of B-cell lines and in PC lines leads to increased cell proliferation and suppression of Ig synthesis. 14 Thus, repression of PAX5 is important for inhibiting B-lymphocyte functions and is required for PC functions. 15,16 Moreover, recent studies demonstrate the oncogenic role of BSAP by mutations or alterations in the expression of PAX5 gene. [17][18][19][20][21] Murine B-lymphocyte-induced maturation protein-1 (BLIMP1), or its human homologue positive regulatory domain I binding factor 1 (PRDI-BF1), is a transcription factor that has been demonstrated to act as a master regulator required 10 and sufficient 22 for the generation and for the prolonged maintenance of PCs. 23 To differentiate into PCs, BLIMP1 reduces B-cell proliferation as a consequence of MYC repression, 24 and decreases B-cell functions as a result of PAX5 repression. 25 An essential gene for PC differentiation indirectly induced by BLIMP1, as well as by IRF4, is XBP1. [25][26][27] Moreover, ...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Human BSAP and BLIMP1 conform an autoregulatory feedback loop

Mora-López

Reales

Brieva

et al. 2007

Blood

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“…The affinity maturation of Abs and differentiation of B cells into Ab-secreting cells (ASC) 3 are crucial components of the immune response. B cells that successfully respond to Ag can differentiate into plasmablasts (short-lived proliferating ASC), into long-lived noncycling Ab-secreting plasma cells, and into memory B cells that can rapidly differentiate into ASC after re-exposure to Ag (1).…”

Section: Initiation Of Antigen Receptor-dependent Differentiation Intomentioning

confidence: 99%

“…A small group of transcription factors expressed in the B cells, including Pax5, Bcl-6, MITF, Ets-1, and BACH2, are repressors of the ASC differentiation program (1,3,7). Pax5 is essential to establish and maintain B cell identity.…”

Section: Initiation Of Antigen Receptor-dependent Differentiation Intomentioning

confidence: 99%

“…It activates many B lineage-specific genes and simultaneously represses many genes associated with stem cell and non-B lineage programs as well as a number of genes involved in ASC differentiation, including Prdm1, the gene encoding B lymphocyte-induced maturation protein 1 (Blimp1), and Xbp-1. Therefore, Pax5 must be repressed to allow ASC differentiation (1)(2)(3). Bcl-6, Ets-1, Spi-B, and BACH2 are also suppressors of ASC development, in part by repressing Blimp1 and Xbp-1 (1,3,7,8).…”

Section: Initiation Of Antigen Receptor-dependent Differentiation Intomentioning

confidence: 99%

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Initiation of Antigen Receptor-Dependent Differentiation into Plasma Cells by Calmodulin Inhibition of E2A

Hauser

Verma-Gaur

Wallenius

et al. 2009

The Journal of Immunology

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Differentiation of B lymphocytes into Ab-secreting plasmablasts and plasma cells is Ag driven. The interaction of Ag with the membrane-bound Ab of the BCR is critical in determining which clones enter the plasma cell response. However, not much is known about the coupling between BCR activation and the shift in transcription factor network from that of a B cell to that of ASC differentiation. Our genome-wide analysis shows that Ab-secreting cell differentiation of mouse B cells is induced by BCR activation through very fast regulatory events from the BCR. We identify activation of IFN regulatory factor-4 and down-regulation of Pax5, Bcl-6, MITF, Ets-1, Fli-1, and Spi-B gene expression as immediate early events. Furthermore, the transcription factor E2A is required for the rapid key down-regulations after BCR activation, and the Ca2+ sensor protein calmodulin has the corresponding regulatory effect as BCR activation. Moreover, mutants in the calmodulin binding site of E2A show that Ca2+ signaling through calmodulin inhibition of E2A is essential for the rapid down-regulation of immediate early genes after BCR activation in initiation of plasma cell differentiation.

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