The Transcription Factor Fli-1 Modulates Marginal Zone and Follicular B Cell Development in Mice

Abstract

Fli-1 belongs to the Ets transcription factor family and is expressed primarily in hematopoietic cells, including most cells active in immunity. To assess the role of Fli-1 in lymphocyte development in vivo, we generated mice that express a truncated Fli-1 protein, lacking the C-terminal transcriptional activation domain (Fli-1ΔCTA). Fli-1ΔCTA/Fli-1ΔCTA mice had significantly fewer splenic follicular B cells, and an increased number of transitional and marginal zone B cells, compared with wild-type controls. Bone marrow reconstitution studies demonstrated that this phenotype is the result of lymphocyte intrinsic effects. Expression of Igα and other genes implicated in B cell development, including Pax-5, E2A, and Egr-1, are reduced, while Id1 and Id2 are increased in Fli-1ΔCTA/Fli-1ΔCTA mice. Proliferation of B cells from Fli-1ΔCTA/Fli-1ΔCTA mice was diminished, although intracellular Ca2+ flux in B cells from Fli-1ΔCTA/Fli-1ΔCTA mice was similar to that of wild-type controls after anti-IgM stimulation. Immune responses and in vitro class switch recombination were also altered in Fli-1ΔCTA/Fli-1ΔCTA mice. Thus, Fli-1 modulates B cell development both centrally and peripherally, resulting in a significant impact on the in vivo immune response.

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

“…Although various studies have described the importance of proteins involved in cell signaling for FO B cell differentiation, few transcription factors have been described that are important for FO versus MZ lineage fate decisions. Notably, one transcription factor previously identified as important for FO B cell differentiation was Fli-1, a member of the extended Ets protein family that includes PU.1, Spi-B, and Spi-C (15). Our experiments establish that PU.1 and Spi-B are important for FO B cell differentiation.…”

“…For flow cytometry, mouse splenocytes were washed after hypotonic lysis with ammonium chloride solution and stained with allophycocyanin-conjugated anti-B220 (RA3-6B2), PE-conjugated anti-CD19 (1D3), PE-Cy5-conjugated anti-IgM (II/41), PE-conjugated anti-CD93 (AA4.1), FITC-conjugated anti-IgD (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), FITC-conjugated anti-CD23 (B3B4), FITC-conjugated anti-CD21 (eBio8D9), FITC-conjugated anti-CD1d (1B1), or biotin-conjugated anti-IL-21R (eBio4A9). All Abs were purchased from eBioscience (San Diego, CA).…”

“…MZ B cell development is impaired in the absence of Notch2 signaling (12,13) as well as by mutation of the E26 transformation-specific (Ets) transcription factor Ets-1 (14). FO B cell development is moderately impaired in the absence of the Ets transcription factor Fli-1 (15). However, more work needs to be done to determine what transcription factors are critical for FO versus MZ B cell differentiation.…”

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

“…33 In mice, FLI1 regulates B-cell differentiation, proliferation, and apoptosis and contributes to the control of marginal zone and follicular B-cell development. 34 In our study, the 11q24.3 gain was observed in both GCB-and ABC-DLBCL. The OCI-Ly7 cell line, the in vitro model bearing the 11q24.3 gain, is usually considered of GCB origin but is more likely representative of a type of DLBCL intermediate between GCB and ABC DLBCL.…”

Transcription Factor ABF-1 Suppresses Plasma Cell Differentiation but Facilitates Memory B Cell Formation

“…Its overexpression in mice leads to B cell hyperplasia and a spontaneous systemic lupus erythematosus-like disease (46,47). More importantly, the proliferation of B cells from Fli1-deficient mice is impaired (48). These combined findings suggested that the diminished cell proliferation resulting from ec- topic expression of ABF-1 in human memory B cells may be partly due to reduced FLI1 expression.…”