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 SOX9
Homo sapiens
 HIF1A
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Mus musculus
 PAX6
Homo sapiens
 Snai2
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Transcription Factor Encyclopedia  BETA
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Overview

SPIB (Spleen focus-forming virus integration site) is a transcription factor of the E26 transformation-specific (Ets) family and is highly homologous to the oncoprotein Spi-1/purine box 1 (PU.1)[1] . ETS proteins share a conserved ETS domain that mediates specific DNA binding. SPIB is a hematopoietic cell-specific transcription factor and expressed in plasmacytoid dendritic cells (pDCs), hematopoietic stem cells (HSCs) and mature B cells [2].

The transcriptional regulation of SPIB appears complex. Multiple transcripts can be expressed from the SPIB gene[1] [3]: a major 1.5kb, a minor 3.7kb and a weakly detected 2.8kb. While in human regulation of SPIB expression is elusive, in mice expression of the Spib gene is driven by two different promoters [3]. The only known transcription factor to drive Spib gene expression is the co-activator OBF-1 (Bob-1, OCA-B) which associates with the transcription factors Oct-1 or Oct-2 on the conserved octamer element present in the promoters of several ubiquitous and lymphoid-specific genes [4].

SPIB when acting as a monomer, binds to purine-rich DNA consensus elements (GGAA/T)[5]. When binding with a partner IRF4, SPIB but also PU.1 regulates gene expression by binding a composite DNA element called ETS/ISRE-consensus element (EICE), which has the consensus sequence 5'-GGAANNGAAA-3' that fuses the ETS-binding motif (5'-GGAA-3') with the IRF4-binding motif (5'-AANNGAAA-3')[6].

SPIB has been shown to be a critical regulator of lineage commitment during human hematopoiesis as its overexpression in CD34+ progenitors cells blocks T-, B-, and NK- cell development (Figure 1)[2]. More importantly SPIB is required for pDCs development in human [7], likely by indirectly promoting the activity of the E-protein E2-2, which is a member of the basic helix-loop-helix (bHLH) family [8]. T cell development is impaired by counteracting the Notch pathway required for GATA-3 upregulation (Figure 2)[9]. In B cells, SPIB blocks the differentiation of memory B cells into antibody secreting plasma cells by direct transcriptional repression of the PRDM1 and XBP1 genes (Figure 3)[10]. In mice, the lack of Spib does not grossly affect hematopoiesis, although mature B cells appear functionally defective [11][12]. Spib is not required for somatic hyper mutations in B cells [13].

Another feature of SPIB is its putative oncogenic role. SPIB transcripts have been found in multiple myeloma cells [14] and overexpression of SPIB due to translocation of SPIB to the Ig heavy-chain locus was detected in an activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cell line [15].This cell line was shown to depend on SPIB for its survival [16].

References
  1. Ray D et al. Characterization of Spi-B, a transcription factor related to the putative oncoprotein Spi-1/PU.1. Mol. Cell. Biol., 12(10):4297-304. (PMID 1406622)
  2. Schotte R et al. The transcription factor Spi-B is expressed in plasmacytoid DC precursors and inhibits T-, B-, and NK-cell development. Blood, 101(3):1015-23. (PMID 12393575)
  3. Chen HM et al. Neutrophils and monocytes express high levels of PU.1 (Spi-1) but not Spi-B. Blood, 85(10):2918-28. (PMID 7742552)
  4. Bartholdy B et al. The Ets factor Spi-B is a direct critical target of the coactivator OBF-1. Proc. Natl. Acad. Sci. U.S.A., 103(31):11665-70. (PMID 16861304)
  5. Su GH et al. The Ets protein Spi-B is expressed exclusively in B cells and T cells during development. J. Exp. Med., 184(1):203-14. (PMID 8691135)
  6. Brass AL et al. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev., 10(18):2335-47. (PMID 8824592)
  7. Schotte R et al. The ETS transcription factor Spi-B is required for human plasmacytoid dendritic cell development. J. Exp. Med., 200(11):1503-9. (PMID 15583020)
  8. Nagasawa M et al. Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix-loop-helix factor E2-2 and the Ets factor Spi-B. Eur. J. Immunol., 38(9):2389-400. (PMID 18792017)
  1. Dontje W et al. Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B. Blood, 107(6):2446-52. (PMID 16317090)
  2. Schmidlin H et al. Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression. Blood, 112(5):1804-12. (PMID 18552212)
  3. Garrett-Sinha LA et al. PU.1 and Spi-B are required for normal B cell receptor-mediated signal transduction. Immunity, 10(4):399-408. (PMID 10229183)
  4. Su GH et al. Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B. EMBO J., 16(23):7118-29. (PMID 9384589)
  5. Kim N et al. The transcription factor Spi-B is not required for somatic hypermutation. Mol. Immunol., 39(10):577-83. (PMID 12431391)
  6. Nagy M et al. Expression of transcription factors Pu.1, Spi-B, Blimp-1, BSAP and oct-2 in normal human plasma cells and in multiple myeloma cells. Br. J. Haematol., 116(2):429-35. (PMID 11841448)
  7. Lenz G et al. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J. Exp. Med., 204(3):633-43. (PMID 17353367)
  8. Lenz G et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc. Natl. Acad. Sci. U.S.A., 105(36):13520-5. (PMID 18765795)
Figures
FIGURE 1 Overview of the role of SpiB in lymphoid development and maturation
Here are depicted the known roles of SpiB during lymphoid lineage commitment and maturation (negative effect of SpiB expression are shown in red [1] [2] [3], positive effect are shown in green [1] and in orange effect only shown in mice [4]).
References
  1. Schotte R et al. The ETS transcription factor Spi-B is required for human plasmacytoid dendritic cell development. J. Exp. Med., 200(11):1503-9. (PMID 15583020)
  2. Schotte R et al. The transcription factor Spi-B is expressed in plasmacytoid DC precursors and inhibits T-, B-, and NK-cell development. Blood, 101(3):1015-23. (PMID 12393575)
  1. Schmidlin H et al. Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression. Blood, 112(5):1804-12. (PMID 18552212)
  2. Lefebvre JM et al. Enforced expression of Spi-B reverses T lineage commitment and blocks beta-selection. J. Immunol., 174(10):6184-94. (PMID 15879115)
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.