Regulation of Follicular B Cell Differentiation by the Related E26 Transformation-Specific Transcription Factors PU.1, Spi-B, and Spi-C

DeKoter, Rodney P.; Geadah, Marc; Khoosal, Sonam; Xu, Li; Thillainadesan, Gobi; Torchia, Joseph; Chin, Shu Shien; Garrett‐Sinha, Lee Ann

doi:10.4049/jimmunol.1001413

Cited by 43 publications

(69 citation statements)

References 54 publications

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“…These results suggest that IL-7R expression and IL-7 signaling plays a role in development of leukemia in DPB mice. Developing B cells express high levels of IL-7Ra, but this receptor is not expressed by mature B cells (51 efficiently differentiate into follicular B cells (31). PU.1 and Spi-B regulate a number of genes required for BCR signaling, including P2Y10, Grap2, and Btk (53,54).…”

Section: Discussionmentioning

confidence: 99%

“…Transient transfection of WEHI-279 cells was performed using electroporation as previously described (31). MIGR1, MIG-3XFLAG-PU.1, and MIG-3XFLAG-Spi-B-infected WEHI-279 clonal cell lines were crosslinked with 1% formaldehyde for 10 min at room temperature.…”

Section: Transient Transfection and Chip Analysismentioning

confidence: 99%

“…MIGR1, MIG-3XFLAG-PU.1, and MIG-3XFLAG-Spi-B-infected WEHI-279 clonal cell lines were crosslinked with 1% formaldehyde for 10 min at room temperature. ChIP was performed as previously described (31). Enrichment was measured using quantitative PCR (qPCR) of DNA immunoprecipitated with anti-FLAG magnetic beads (Sigma-Aldrich), using primers indicated in Supplemental Table I.…”

Section: Transient Transfection and Chip Analysismentioning

confidence: 99%

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Regulation of B Cell Linker Protein Transcription by PU.1 and Spi-B in Murine B Cell Acute Lymphoblastic Leukemia

Sokalski

Hotke

et al. 2012

The Journal of Immunology

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B cell acute lymphoblastic leukemia (B-ALL) is frequently associated with mutations or chromosomal translocations of genes encoding transcription factors. Conditional deletion of genes encoding the E26-transformation–specific transcription factors, PU.1 and Spi-B, in B cells (ΔPB mice) leads to B-ALL in mice at 100% incidence rate and with a median survival of 21 wk. We hypothesized that PU.1 and Spi-B may redundantly activate transcription of genes encoding tumor suppressors in the B cell lineage. Characterization of aging ΔPB mice showed that leukemia cells expressing IL-7R were found in enlarged thymuses. IL-7R–expressing B-ALL cells grew in culture in response to IL-7 and could be maintained as cell lines. Cultured ΔPB cells expressed reduced levels of B cell linker protein (BLNK), a known tumor suppressor gene, compared with controls. The Blnk promoter contained a predicted PU.1 and/or Spi-B binding site that was required for promoter activity and occupied by PU.1 and/or Spi-B as determined by chromatin immunoprecipitation. Restoration of BLNK expression in cultured ΔPB cells opposed IL-7–dependent proliferation and induced early apoptosis. We conclude that the tumor suppressor BLNK is a target of transcriptional activation by PU.1 and Spi-B in the B cell lineage.

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Section: Discussionmentioning

confidence: 99%

Section: Transient Transfection and Chip Analysismentioning

confidence: 99%

Section: Transient Transfection and Chip Analysismentioning

confidence: 99%

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Regulation of B Cell Linker Protein Transcription by PU.1 and Spi-B in Murine B Cell Acute Lymphoblastic Leukemia

Sokalski

Hotke

et al. 2012

The Journal of Immunology

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“…To replicate in glial cells, JCV has to modify its transcriptional control region, but once the altered regulatory These are not the final page numbers region is present, JCV can reactivate and replicate using host transcription factors such as those described in glial cells, but also in B cells [20]. In addition, the complex processes used by B cells to generate immunoglobulins may also facilitate the modification of the regulatory region of JCV [37,38]. In this context, it is interesting to note that natalizumab up-regulates several genes involved in B-cell differentiation including transcription factors that are able to bind JCV and that the spleen [39,40], the most important reservoir of memory B cells, is the tissue that most frequently tests positive for JCV DNA and harbors the highest diversity of sequence rearrangements within the JCV regulatory region [19,41,42].…”

Section: /Cd8mentioning

confidence: 99%

Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis

et al. 2011

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Natalizumab, an antibody against the a4 subunit of a4 integrins, has been approved for multiple sclerosis (MS) therapy based on its high efficacy and safety profile. However, natalizumab has been associated with the development of progressive multifocal leukoencephalopathy (PML), a disorder caused by JC virus (JCV) infection. In order to improve our understanding of the mechanism of action of natalizumab and to identify possible risk factors for PML development, we have characterized in detail the cell blood composition in MS patients treated with natalizumab for more than 30 months. Natalizumab induced the release of lymphoid-but not myeloid precursor cells, which resulted in a chronic increase of T-, NK-and particularly B cells. While the percentage of recent thymic emigrants (RTE), naïve, effector or memory T cells remained unchanged during treatment, a higher percentage of memory-and marginal zone (MZ)-like, but not of naïve B cells, was observed, which most likely is due to a decreased retention of these cells within the splenic MZ. The ability of natalizumab to influence B-cell migration and homeostasis through the splenic MZ, where JCV has been detected, adds to the list of natalizumab effects and may contribute to PML development by disseminating JCV.Key words: B cells . Multiple sclerosis . Natalizumab . Progressive multifocal leukoencephalopathy Supporting Information available online Introduction Natalizumab, a monoclonal antibody against the a4 subunit (CD49d) of a4 integrins (a4b1 and a4b7), has been approved for multiple sclerosis (MS) therapy based on its high efficacy and good safety profile. The a4b1 integrin is expressed by all leukocytes except neutrophils and serves as an adhesion molecule mediating attachment to endothelial cells. Natalizumab prevents transmigration of leukocytes across the blood-brain barrier by blocking a4b1 integrin/vascular cell adhesion molecule-1 (VCAM-1) interaction [1][2][3][4][5]. a4b1 integrin also serves as a retention signal for hematopoietic precursor cells in the BM, and consequently it has been demonstrated that natalizumab mobilizes hematopoietic precursor cells from the BM [6][7][8]. Natalizumab treatment also induces significant phenotypic changes in the immune cell composition of peripheral blood such as an increase Eur. J. Immunol. 2012. 42: 790-798 790 in T-, NK-and especially B cells and a decrease in monocytes [9][10][11][12]. These changes have been attributed to a higher release of hematopoietic precursor cells from the BM as well as a reduced migration of leukocytes into the central nervous system (CNS). However, since a4 integrin ligands are also expressed in secondary lymphoid tissues, such as spleen and gut-associated lymphoid tissue, natalizumab may influence the immune cell composition in the blood by affecting homeostasis, homing and migration of leukocytes through secondary lymphoid organs as well.Natalizumab treatment can lead to progressive multifocal leukoencephalopathy (PML), a demyelinating disorder of the CNS caused by JC virus (JCV...

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“…Of these genes, Spib and Flt3l (Flt3 ligand) are encoded on chromosome 7 between 51 and 53 Mb, comprised within the NOD.NZW-Chr7 congenic interval contributing to the size of the pDC compartment. Spi-B is a transcription factor implicated in the differentiation of both B cells and pDC (11,28,29), in which overexpression of Spi-B in hematopoietic progenitors leads to an increase in pDC number (11). In addition, Flt3L promotes the differentiation of all DC subsets and is known to increase pDC number (30).…”

Section: Discussionmentioning

confidence: 99%

The Size of the Plasmacytoid Dendritic Cell Compartment Is a Multigenic Trait Dominated by a Locus on Mouse Chromosome 7

Pelletier

Guimont-Desrochers

Ashton

et al. 2012

The Journal of Immunology

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Plasmacytoid dendritic cells (pDC) compose one of the many distinct dendritic cell subsets. The primary function of pDC is to potently produce type 1 IFNs upon stimulation, which is highly relevant in antiviral responses. Consequently, the ability to manipulate the size of the pDC compartment in vivo may increase the capacity to clear viral infections. In an attempt to identify genetic loci affecting the size of the pDC compartment, defined by both the proportion and absolute number of pDC, we undertook an unbiased genetic approach. Linkage analysis using inbred mouse strains identified a locus on chromosome 7 (Pdcc1) significantly linked to both the proportion and the absolute number of pDC in the spleen. Moreover, loci on either chromosome 11 (Pdcc2) or 9 (Pdcc3) modified the effect of Pdcc1 on chromosome 7 for the proportion and absolute number of pDC, respectively. Further analysis using mice congenic for chromosome 7 confirmed Pdcc1, demonstrating that variation within this genetic interval can regulate the size of the pDC compartment. Finally, mixed bone marrow chimera experiments showed that both the proportion and the absolute number of pDC are regulated by cell-intrinsic hematopoietic factors. Our findings highlight the multigenic regulation of the size of the pDC compartment and will facilitate the identification of genes linked to this trait.

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Regulation of Follicular B Cell Differentiation by the Related E26 Transformation-Specific Transcription Factors PU.1, Spi-B, and Spi-C

Abstract: Material

Cited by 43 publications

References 54 publications

Regulation of B Cell Linker Protein Transcription by PU.1 and Spi-B in Murine B Cell Acute Lymphoblastic Leukemia

Regulation of B Cell Linker Protein Transcription by PU.1 and Spi-B in Murine B Cell Acute Lymphoblastic Leukemia

Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis

The Size of the Plasmacytoid Dendritic Cell Compartment Is a Multigenic Trait Dominated by a Locus on Mouse Chromosome 7

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