scholarly journals Regulation of Marginal Zone B Cell Differentiation By microRNA-146a Via the Numb-Notch Pathway

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3701-3701
Author(s):  
Jennifer K King ◽  
Nolan Ung ◽  
May Paing ◽  
Jorge R. Contreras ◽  
Michael O. Alberti ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Marginal Zone ◽  
Conflicts Of Interest ◽  
Regulatory Protein ◽  
Notch Pathway ◽  
Cell Development ◽  
B Cell Differentiation

Abstract B cell development in bone marrow is followed by specification into spleen subsets, including marginal zone (MZ) cells. MZ require elaboration of distinct gene expression programs for development. Given their role in gene regulation, its not surprising that microRNAs (miRNAs) influence cell development. Recent work demonstrated that deficiency of NF-κB feedback regulator, Mir146 (miR-146a), led to a range of hematopoietic phenotypes, but B cells have not been extensively characterized. Here, we found miR-146a deficient mice demonstrate a reduction in MZ B cells, likely from a T cell independent developmental block. Utilizing comparative analysis of developmental stage-specific transcriptomes, we show MZ cell differentiation was impaired due to decreases in Notch2 signaling. Further, we discovered that the cell-fate regulatory protein, Numb, is a direct target of miR-146a, and its derepression in miR-146a deficient B cells underlies the decreases in Notch2. Our studies reveal miR-146a-dependent B cell phenotypes regulated by the Numb-Notch2 pathway. Disclosures No relevant conflicts of interest to declare.

Programming of marginal zone B-cell fate by basic Krüppel-like factor (BKLF/KLF3)

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3780-3792 ◽  
Author(s):  
Gleb Turchinovich ◽  
Thi Thanh Vu ◽  
Friederike Frommer ◽  
Jan Kranich ◽  
Sonja Schmid ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Marginal Zone ◽  
Nuclear Factor Κb ◽  
Genetic Alterations ◽  
B Cell Differentiation ◽  
Humoral Immune ◽  
B Cell Subsets

Abstract Splenic marginal zone (MZ) B cells are a lineage distinct from follicular and peritoneal B1 B cells. They are located next to the marginal sinus where blood is released. Here they pick up antigens and shuttle the load onto follicular dendritic cells inside the follicle. On activation, MZ B cells rapidly differentiate into plasmablasts secreting antibodies, thereby mediating humoral immune responses against blood-borne type 2 T-independent antigens. As Krüppel-like factors are implicated in cell differentiation/function in various tissues, we studied the function of basic Krüppel-like factor (BKLF/KLF3) in B cells. Whereas B-cell development in the bone marrow of KLF3-transgenic mice was unaffected, MZ B-cell numbers in spleen were increased considerably. As revealed in chimeric mice, this occurred cell autonomously, increasing both MZ and peritoneal B1 B-cell subsets. Comparing KLF3-transgenic and nontransgenic follicular B cells by RNA-microarray revealed that KLF3 regulates a subset of genes that was similarly up-regulated/down-regulated on normal MZ B-cell differentiation. Indeed, KLF3 expression overcame the lack of MZ B cells caused by different genetic alterations, such as CD19-deficiency or blockade of B-cell activating factor-receptor signaling, indicating that KLF3 may complement alternative nuclear factor-κB signaling. Thus, KLF3 is a driving force toward MZ B-cell maturation.

scholarly journals Increased Frequency of Pre–Pro B Cells in the Bone Marrow of New Zealand Black (NZB) Mice: Implications for aDevelopmental Block in B Cell Differentiation

2002 ◽  
Vol 9 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Zhe-Xiong Lian ◽  
Hiroto Kita ◽  
Tomoyuki Okada ◽  
Tom Hsu ◽  
Leonard D. Shultz ◽  
...  
Keyword(s):  
New Zealand ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Differentiation Markers ◽  
Cell Stage

Reductions in populations of both Pre-B cell (Hardy fractions D) and Pro-B cells (Hardy fractions B–C) have been described in association with murine lupus. Recent studies of B cell populations, based on evaluation of B cell differentiation markers, now allow the enumeration and enrichment of other stage specific precursor cells. In this study we report detailed analysis of the ontogeny of B cell lineage subsets in New Zealand black (NZB) and control strains of mice. Our data suggest that B cell development in NZB mice is partially arrested at the fraction A Pre–Pro B cell stage. This arrest at the Pre-Pro B cell stage is secondary to prolonged lifespan and greater resistance to spontaneous apoptosis. In addition, expression of the gene encoding the critical B cell development transcription factor BSAP is reduced in the Pre–Pro B cell stage in NZB mice. This impairment may influence subsequent B cell development to later stages, and thereby accounts for the down-regulation of the B cell receptor componentIgα(mb-1). Furthermore, levels of expression of theRug2, λ5andIgβ(B29) genes are also reduced in Pre–Pro B cells of NZB mice. The decreased frequency of precursor B cells in the Pre–Pro B cell population occurs at the most primitive stage of B cell differentiation.

scholarly journals Complete Block of Early B Cell Differentiation in Mice Lacking the Endosomal Adaptor Protein p14

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1026-1026
Author(s):  
Marcin Lyszkiewicz ◽  
Daniel Kotlarz ◽  
Natalia Zietara ◽  
Gudrun Brandes ◽  
Jana Diestelhorst ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Adaptor Protein ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Knock Out ◽  
And Function

Abstract Human primary immunodeficiency caused by a point mutation in the 3' untranslated region of the endosomal adaptor protein p14 (also known as Lamtor2) resulted in severely impaired function of neutrophils, B cells, T cells and melanocytes. However, complexity of the phenotype and scarcity of human material preclude in-depth studies. Therefore, to gain insight into the role of p14 in B cell development and function, we generated loxP conditional knock-out mice. Using mb-1-Cre mice we demonstrated that loss of p14 at the preB1 stage lead to a complete block of B cell development, resulting in the absence of IgM-positive B cells. Further, to test the significance of p14 deficiency in peripheral organs, we took advantage of CD19-Cre mice, which have limited efficiency in deleting target genes in the bone marrow, but reach up to 95% efficiency in spleen. Thus, we could demonstrate that later in B cell development, p14 was essential for the generation and activation of mature B lymphocytes. While B1 cell development was maintained, splenic follicular B cells were massively reduced in the absence of p14. Furthermore, activation of B cell receptor (BCR) resulted in impaired intracellular signalling and proliferation of p14 deficient B cells. In particular, lack of p14 lead to delayed internalization of BCR and endosomal processing associated with impaired mobilization of Ca++ from intracellular stores as well as aberrant phosphorylation of BCR-associated kinases. In conclusion, our data revealed that p14 is a critical regulator of B cell development and function, which acts by modulating BCR signalling. Disclosures No relevant conflicts of interest to declare.

Mir-126 and Mir-195-Mediated Control of B Cell Fate in Leukemic and Normal Cells As a Potential Alternative for Transcriptional Factor

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3533-3533
Author(s):  
Ai Kotani ◽  
Kazuki Okuyama ◽  
Bidisha Chanda ◽  
Tomokatsu Ikawa ◽  
Hiroshi Kawamoto ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Cell Fate ◽  
Conflicts Of Interest ◽  
Transcriptional Factors ◽  
Transcriptional Factor ◽  
Leukemic Cells ◽  
B Cell Differentiation ◽  
Cell Stage ◽  
Exogenous Expression

Abstract Abstract 3533 microRNAs (miRNAs) control many developmental and physiological processes. However, it is assumed to work as a fine tuner in cell fate determination, which has been shown to be regulated by transcription factors. Here, we challenge this canonical notion. miR-126 is downregulated in MLL-AF4 ALL, biphenotypic leukemia expressing both B cell and myeloid markers, compared with other types of ALLs. CD19 and CD20, B cell differentiation markers, were upregulated when miR-126 is reexpressed in MLL-AF4 ALLs (Figure 1). Interestingly, we found that miR-126, in leukemic cells, induces B cell differentiation (Figure 2a) without changing the expression of E2A, EBF1, or PAX5, (Figure 2b) which are assumed to be critical regulators of B cell development indicating that miR-126 induced B cell differentiation independently of transcriptional factors, such as PAX5, E2A, and EBF1. To test the hypothesis, we tried to rescue block of B cell differentiation in EBF1 knock-out hematopoietic progenitor cells (EBF1 KO HPCs) by exogenous expression of miR-126. As a result, significant upregulation of B cell markers, such as B220, RAG1/2, and CD79a/b was induced by miR-126 in EBF1 KO HPCs which show complete block at pre-pro B cell stage.(Figure 3a) Moreover, miR-126 increased cell proliferation, indicating EBF1 KO HPCs differentiate into large preB cells. Moreover, miR-195, which is upregulated toward pro B cells then downregulated in B cell differentiation, also can partially rescue block of B cell differentiation in EBF1 KO HPCs. (Figure 3b) The block in B lymphopoiesis imposed by the absence of E2A or Pax5 can be overcome by exogenous expression of EBF1. Conversely E2A or Pax5 failed to compensate the effect of EBF1. Thereafter miR-126 and miR-195 potentiates to play more roles than E2A or Pax5 in this system and act as more than a fine tuner in B cell differentiation. Our results elucidate a novel mechanism for the regulation of cell fate independent of transcriptional factor, establish an important role for miRNAs in mammalian lineage specification, and suggest that miRNA could be a new possible therapeutic target for dedifferentiation induced by deregulation of transcriptional factors in ALL, which calls for further studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription

2017 ◽  
Vol 214 (7) ◽  
pp. 2059-2071 ◽  
Author(s):  
Kenia Ubieta ◽  
Mireia Garcia ◽  
Bettina Grötsch ◽  
Steffen Uebe ◽  
Georg F. Weber ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Gene Profiling ◽  
B Cell Differentiation

The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7–stimulated pro–B cell cultures revealed a reduced differentiation from large pre–B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2–deficient B cells. Moreover, expression of IL7Rα and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro–B cell proliferation and small pre–B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2–deficient pro–B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages.

scholarly journals B-1 Cell Development: Evidence for an Uncommitted Immunoglobulin (Ig)M+ B Cell Precursor in B-1 Cell Differentiation

1998 ◽  
Vol 187 (8) ◽  
pp. 1325-1334 ◽  
Author(s):  
Stephen H. Clarke ◽  
Larry W. Arnold
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Lineage ◽  
Signal Transduction Pathway ◽  
Cell Receptor ◽  
Cell Development ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Receptor Signal

Murine phosphatidyl choline (PtC)–specific B cells in normal mice belong exclusively to the B-1 subset. Analysis of anti-PtC (VH12 and VH12/Vκ4) transgenic (Tg) mice indicates that exclusion from B-0 (also known as B-2) occurs after immunoglobulin gene rearrangement. This predicts that PtC-specific B-0 cells are generated, but subsequently eliminated by either apoptosis or differentiation to B-1. To investigate the mechanism of exclusion, PtC-specific B cell differentiation was examined in mice expressing the X-linked immunodeficiency (xid) mutation. xid mice lack functional Bruton's tyrosine kinase (Btk), a component of the B cell receptor signal transduction pathway, and are deficient in B-1 cell development. We find in C57BL/ 6.xid mice that VH12 pre-BII cell selection is normal and that PtC-specific B cells undergo modest clonal expansion. However, the majority of splenic PtC-specific B cells in anti-PtC Tg/xid mice are B-0, rather than B-1 as in their non-xid counterparts. These data indicate that PtC-specific B-0 cell generation precedes segregation as predicted, and that Btk function is required for efficient segregation to B-1. Since xid mice exhibit defective B cell differentiation, not programmed cell death, these data are most consistent with an inability of PtC-specific B-0 cells to convert to B-1 and a single B cell lineage.

The MiR-23a MicroRNA Cluster Inhibits B Cell Development.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1465-1465
Author(s):  
Jason Mullenix ◽  
Kimi Y Kong ◽  
Kristin Severns Owens ◽  
Jason Rogers ◽  
Shannon FitzPatrick ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Conflicts Of Interest ◽  
Myeloid Cells ◽  
Mature Mirnas ◽  
Cell Development ◽  
B Cell Development

Abstract Abstract 1465 Poster Board I-488 The miR-23a microRNA (miRNAs) cluster inhibits both [ITALIC]in vitro[/ITALIC] and [ITALIC]in vivo[/ITALIC] B cell development. When murine hematopoietic progenitor cells expressing the 23a cluster miRNAs were cultured in B cell promoting conditions we observed over a five-fold decrease in the generation of CD19+ B cells compared to control cultures. Conversely, we observed over a five-fold increase in CD11b+ myeloid cells. When irradiated mice were transplanted with bone marrow expressing the miR-23a cluster we observed a two-fold decrease in bone marrow and splenic B cells, 8 weeks post-transplant compared to control mice. The miR-23a cluster codes for a single pri-transcript, which when processed yields three mature miRNAs: miR-23a, miR-27a, and miR-24-2. All three mature miRNAs are more abundant in myeloid cells compared to other hematopoietic cells. In vitro miR-24 alone is necessary and sufficient to inhibit B cell development. The promoter for the cluster contains conserved binding sites for the essential myeloid transcription factors PU.1 and C/EBP alpha. Chromatin immunoprecipitations demonstrated that PU.1 and C/EBP alpha are associated with the promoter in myeloid cells. In addition, C/EBP alpha is bound to several highly conserved regions upstream of the promoter. Both PU.1 and C/EBP alpha promote myeloid development at the expense of lymphopoiesis. Our work suggests that the miR-23a cluster may be a critical downstream target of PU.1 and C/EBP alpha in the specification of myeloid cell fate. Although miRNAs have been identified downstream of PU.1 and C/EBP alpha in mediating the development of monocytes and granulocytes, the 23a cluster is the first downstream miRNA target implicated in the regulating lymphoid cell fate acquisition. We are currently identifying targets of miR-24 that may mediate the inhibitory effect on B lymphopoiesis. Disclosures No relevant conflicts of interest to declare.

Involvement of Ets Factor Spi-B, E Protein E2-2, and Id2 in Waldenström's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2946-2946
Author(s):  
Yangsheng Zhou ◽  
Xia Liu ◽  
Lian Xu ◽  
Zachary Hunter ◽  
Jenny Sun ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
B Cell Differentiation ◽  
Protein Activity ◽  
E Proteins ◽  
E Protein ◽  
Nuclear Extracts

Abstract Abstract 2946 Poster Board II-922 Waldenström's macroglobulinemia (WM) is an incurable B cell disorder with a lymphoplasmacytic infiltrate in the bone marrow (BM) and IgM monoclonal gammopathy. WM tumor cells show variable differentiation, ranging from mature B-cells to plasma cells, which likely results from failure to fully undergo differentiation. In this study, we analyzed the expression of several genes involved in B cell differentiation by real time RT-PCR, such as Ets factors, the basic helix-loop-helix (bHLH) E proteins, as well as the inhibitors of DNA binding (Id) proteins which antagonize E protein activity. Comparison of BM CD19+ B cells obtained from 13 WM patients with 6 age-matched healthy donors showed that expression of the Ets factor Spi-B was increased four-fold, while Id2 was decreased three-fold. However, transcript levels of E proteins were similar between the two groups. Transduction of Spi-B in BCWM.1 WM cells resulted in two-fold higher levels of Id2 and five-fold lower levels of E2-2 compared with control. Id2 transduced BCWM.1 cells expressed two-fold lower levels of E2-2 and Spi-B. Taken together, these results implicate that increased expression of Spi-B alone cannot suppress Id2 transcription in the absence of E2-2 activity. Interestingly, overexpressing Spi-B while concomitantly knocking down Id2 increased the expression of the XBP-1 splicing isoform 2.5-fold without changing levels of Blimp-1 and IRF4. Moreover, inhibition of Spi-B expression by RNA interference or forced expression of Id2 in transduced BCWM.1 cells induced a significant decrease of anti-apoptotic Bcl-2. Importantly, we also showed that Spi-B co-immunoprecipated with Blimp-1 in nuclear extracts. Collectively, these data suggest that the regulatory network of the Spi-B, E2-2, and Id2 plays an essential role in B cell differentiation as well as the pathogenesis of WM, and suggests that Spi-B overexpression may block WM cell differentiation by sequestration of Blimp-1 while promoting tumor cell survival though up-regulation of Bcl-2. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Autoreactive T cells preferentially drive differentiation of non-responsive memory B cells at the expense of germinal center maintenance

2018 ◽  
Author(s):  
Rajiv W Jain ◽  
Kate A Parham ◽  
Yodit Tesfagiorgis ◽  
Heather C Craig ◽  
Emiliano Romanchik ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Germinal Center ◽  
Memory B Cells ◽  
B Cell Differentiation ◽  
Cell Fate Decisions ◽  
The Status

AbstractB cell fate decisions within a germinal center (GC) are critical to determining the outcome of the immune response to a given antigen. Here, we characterize GC kinetics and B cell fate choices in a response to the autoantigen myelin oligodendrocyte glycoprotein (MOG), and compare them the response to a standard model foreign antigen (NP-haptenated ovalbumin, NPOVA). Both antigens generated productive primary responses, as evidenced by GC development, circulating antigen-specific antibodies, and differentiation of memory B cells. However, in the MOG response the status of the cognate T cell partner drove preferential B cell differentiation to a memory phenotype at the expense of GC maintenance, resulting in a truncated GC. Reduced plasma cell differentiation was largely independent of T cell influence. Interestingly, memory B cells formed in the MOG GC were unresponsive to secondary challenge and this could not be overcome with T cell help.

LRF Critically Regulates Mature B Cell Fate and Germinal Center Response Via Notch-Dependent and -Independent Mechanisms.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1961-1961
Author(s):  
Nagisa Sakurai ◽  
Manami Maeda ◽  
Sung-UK Lee ◽  
Toshiki Saito ◽  
Shigeru Chiba ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Knockout Mice ◽  
Critical Role ◽  
Notch Pathway ◽  
Cell Development ◽  
B Cell Development ◽  
Secondary Lymphoid Organs

Abstract Abstract 1961 Poster Board I-984 LRF (Leukemia/Lymphoma Related Factor) is a transcriptional repressor originally identified as an interaction partner of the oncoprotein BCL6 (B cell Lymphoma 6). We previously found that LRF acts as a proto-oncogene by repressing tumor suppressor ARF (Alternative Reading Frame, also known as p19 in mice and p14 in humans) and is highly expressed in 60-80% of human Non-Hodgkin Lymphoma (NHL) cases (Maeda et al., Nature 2005). LRF was also found to be indispensable for hematopoietic stem cells (HSCs) to commit to the B cell lineage by opposing Notch function (Maeda et al., Science 2007). Considering that: 1) LRF is normally expressed in Germinal Center B cells (GCB) and overexpressed in NHL tissues and 2) LRF opposes Notch function to maintain normal B cell fate at HSC/progenitor levels, we explored the role of LRF in B cell development and its functional interaction with the Notch pathway in vivo. Upon T cell dependent (TD) immunization, GC formation was severely impaired in secondary lymphoid organs of B cell specific LRF conditional knockout mice (LRFflox/flox mb1-Cre+). While a GC reaction was robustly induced in control mice upon immunization, only few GCB cells were noted in secondary lymphoid organs of LRFflox/flox mb1-Cre+ mice. To assess functional significance of LRF loss in antigen response in vivo, titers of class-switched immunoglobulin (Ig) were measured in the serum; baseline serum titers of IgG1, IgG2b and IgG3 were perturbed, and the primary and secondary antibody response against the TD antigen was impaired in LRFflox/flox mb1-Cre+ mice. Absolute numbers of memory B cells and long-lived BM plasma cells were reduced in LRFflox/flox mb1-Cre+ mice 20 wk after immunization. To determine the cause of defective GC formation, apoptosis and proliferation of GCB cells were examined by FACS. While proportions of apoptotic (AnnexinV positive) GCB cells were similar, regardless of genotypes, LRF deficient GCB cells failed to proliferate upon antigen stimuli. Short-term kinetic analysis demonstrated 5-ethynyl-2'-deoxyuridine (EdU) incorporation was markedly decreased in LRF deficient GCB cells and that the proportion of GCB cells in S phase was reduced in LRFflox/flox mb1-Cre+ mice. In agreement with these findings, quantitative RT-PCR analysis in FACS-sorted GCB cells demonstrated up-regulation of p19Arf and p21, but not p53, mRNA levels in LRF deficient GCB cells. Up-regulation of p19Arf protein levels was also observed in Western Blots. Furthermore, microarray analysis and subsequent Gene Set Enrichment Analysis in FACS-sorted GCB cells showed signatures of defective proliferation, further implicating a critical role for LRF in GCB cell proliferation. Signals mediated by Notch2 are necessary for transitional B cells to commit to the marginal zone B cells (MZB). Inactivation of a component of the Notch pathway in mice resulted in no MZB development and increased follicular B cells (FOB). On the contrary, deletion of the MINT/SHARP gene, a suppressor of Notch signaling, lead to increase of MZB cells and concomitant reduction of FOB cells, indicating that Notch induces MZB cell fate at the transitional B cell stage. While B cell development in the BM was grossly normal, a reduction of FOB cells and a concomitant increase of MZB cells were observed in LRFflox/flox mb1-Cre+ mice. Since the phenotype was reminiscent of that seen in MINT/SHARP knockout mice and opposite to that observed in Notch2 knockout mice, we hypothesized that LRF antagonizes Notch2 mediated signal during the FOB vs. MZB fate determination process. To test this, LRF/Notch2 double knockout mice (LRFflox/flox Notch2flox/flox mb1-Cre+) were established and their mature B cell compartments analyzed. As expected, loss of the Notch2 gene led to an increase of FOB cells and decrease of MZB in LRFflox/flox mb1-Cre+ mice, suggesting that LRF regulates FOB vs. MZB fate in a Notch2 dependent manner. However, Notch2 deficiency did not restore GC formation in LRFflox/flox mb1-Cre+ mice. In summary, our genetic studies strongly indicate that the proto-oncogene LRF is required for normal mature B cell development and function via distinct mechanisms. We propose that LRF is necessary for mature B cell fate by blocking Notch2-mediated signals and plays a critical role in GCB cell proliferation via suppressing p19Arf mediated cell cycle arrests. Our findings provide a further rational for targeting LRF for the treatment of B cell malignancies as well as autoimmune diseases. Disclosures: No relevant conflicts of interest to declare.

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