The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

Interleukin (IL)-7 is a stromal cell–derived cytokine required for the survival, proliferation, and differentiation of B cell precursors. Members of the Bcl-2 family of proteins are known to have profound effects on lymphocyte survival, but not lymphocyte differentiation. To distinguish the relative dependence on IL-7 of B cell precursor survival versus B cell differentiation, the combined effects of lack of IL-7 and lack of the proapoptotic Bcl-2 relative, Bim, were studied. Bim is expressed to varying degrees in all B cell precursors and B cells. Lack of Bim compensated for lack of IL-7 in the survival of pro–, pre–, and immature B cells; however, lack of Bim did not substitute for the requirement for IL-7 in B cell precursor differentiation or B cell precursor proliferation. Precursor B cell survival is more dependent on sufficient levels of IL-7 than precursor B cell differentiation because the number of B cells and their precursors were reduced by half in mice heterozygous for IL-7 expression, but were restored to normal numbers in mice also lacking Bim. Hence, Bim and IL-7 work together to control the survival of B cell precursors and the number of B cells that exist in animals.

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Ras Mediates Effector Pathways Responsible for Pre-B Cell Survival, Which Is Essential for the Developmental Progression to the Late Pre-B Cell Stage

Journal of Experimental Medicine ◽

10.1084/jem.192.2.171 ◽

2000 ◽

Vol 192 (2) ◽

pp. 171-182 ◽

Cited By ~ 39

Author(s):

Hitoshi Nagaoka ◽

Yoshimasa Takahashi ◽

Reiko Hayashi ◽

Tohru Nakamura ◽

Kumiko Ishii ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Survival ◽

Chain Gene ◽

B Cell Differentiation ◽

Antigen Receptors ◽

Cell Stage ◽

Light Chain Gene ◽

B Cell Survival ◽

Effector Pathways

Ras is essential for the transition from early B cell precursors to the pro-B stage, and is considered to be involved in the signal cascade mediated by pre-B cell antigen receptors. To examine the role of p21ras in the late stage of B cell differentiation, we established transgenic mice (TG) expressing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras) in B lineage cells at high levels after the early B cell precursor stage. Expression of p21Asn-17 Ha-ras was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. Inhibition of p21ras activity markedly reduced the life span of pre-B cells, due, at least in part, to downregulation of the expression of an antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21ras activity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reduction in the number of late pre-B cells undergoing immunoglobulin light chain gene (IgL) rearrangement and progressing to immature B cells. These results suggest that p21ras mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.

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Deregulated PAX-5 Transcription From a TranslocatedIgH Promoter in Marginal Zone Lymphoma

Blood ◽

10.1182/blood.v92.10.3865 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3865-3878 ◽

Cited By ~ 62

Author(s):

Aline M. Morrison ◽

Ulrich Jäger ◽

Andreas Chott ◽

Michael Schebesta ◽

Oskar A. Haas ◽

...

Keyword(s):

Cell Differentiation ◽

B Cell ◽

Marginal Zone ◽

B Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Chain Gene ◽

Splenic Marginal Zone Lymphoma ◽

Derivative Chromosome ◽

B Cell Differentiation ◽

Loss Of Function

Abstract The PAX-5 gene codes for the transcription factor BSAP, which is expressed throughout B-cell development. Although loss-of-function mutation in the mouse showed an essential role forPax-5 in early B lymphopoiesis, gain-of-function mutations have implicated the human PAX-5 gene in the control of late B-cell differentiation. PAX-5 (on 9p13) has been involved together with the immunoglobulin heavy-chain (IgH) gene (on 14q32) in the recurring t(9;14)(p13;q32) translocation that is characteristic of small lymphocytic lymphoma with plasmacytoid differentiation. Here we have characterized a complex t(2;9;14)(p12;p13;q32) translocation present in a closely related non-Hodgkin’s lymphoma referred to as splenic marginal zone lymphoma (MZL). In this MZL-1 translocation, the two promoters of PAX-5 were replaced on the derivative chromosome 14 by an immunoglobulin switch Sμ promoter that was linked to the structural PAX-5 gene upstream of its translation initiation codon in exon 1B. Expression analyses confirmed thatPAX-5 transcription was upregulated due to efficient initiation at the Sμ promoter in the malignant B lymphocytes of patient MZL-1. For comparison we have analyzed PAX-5 expression in another B-cell lymphoma, KIS-1, indicating that transcription from the distalPAX-5 promoter was increased in this tumor in agreement with the previously characterized translocation of the immunoglobulin Eμ enhancer adjacent to PAX-5 exon 1A. In both lymphomas, the J-chain gene, which is thought to be under negative control by BSAP, was not expressed, whereas transcription of the putative target genep53 was unaffected by PAX-5 overexpression. Together these data indicate that the t(9;14)(p13;q32) translocation contributes to lymphoma formation as a regulatory mutation that leads to increasedPAX-5 expression in late B-cell differentiation due to promoter replacement or enhancer insertion.

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Monocytoid/marginal zone B-cell differentiation in follicle centre cell lymphoma

Histopathology ◽

10.1111/j.1365-2559.1996.tb01392.x ◽

1996 ◽

Vol 29 (3) ◽

pp. 201-208 ◽

Cited By ~ 35

Author(s):

U. SCHMID ◽

S.B. COGLIATTI ◽

T.C. DISS ◽

P.G. ISSACSON

Keyword(s):

Cell Differentiation ◽

B Cell ◽

Marginal Zone ◽

Cell Lymphoma ◽

B Cell Differentiation

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Regulation of Marginal Zone B-Cell Differentiation by MicroRNA-146a

Frontiers in Immunology ◽

10.3389/fimmu.2016.00670 ◽

2017 ◽

Vol 7 ◽

Cited By ~ 5

Author(s):

Jennifer K. King ◽

Nolan M. Ung ◽

May H. Paing ◽

Jorge R. Contreras ◽

Michael O. Alberti ◽

...

Keyword(s):

Cell Differentiation ◽

B Cell ◽

Marginal Zone ◽

B Cell Differentiation

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

Blood ◽

10.1182/blood.v128.22.3701.3701 ◽

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.

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

Blood ◽

10.1182/blood-2010-09-308742 ◽

2011 ◽

Vol 117 (14) ◽

pp. 3780-3792 ◽

Cited By ~ 20

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.

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Junctional Adhesion Molecule C (JAM-C) Constitutes a New Marker for the Differential Diagnosis of B Cell Lymphomas.

Blood ◽

10.1182/blood.v114.22.3940.3940 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3940-3940

Author(s):

Thomas Matthes ◽

Christiane Ody ◽

Beat Imhof ◽

Carmen Donate ◽

Dominique Cossali ◽

...

Keyword(s):

Flow Cytometry ◽

Differential Diagnosis ◽

Cell Differentiation ◽

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Marginal Zone ◽

Plasma Cells ◽

B Cell Differentiation ◽

B Cell Lymphomas

Abstract Abstract 3940 Poster Board III-876 Introduction Differentiation of naïve B cells into plasma cells or memory cells occurs in the germinal centres (GC) of lymph follicles or alternatively in the marginal zone via a GC- and T cell independent pathway. It is currently assumed that B cell lymphomas correspond to normal B cell differentiation stages, but the precise correlation of several B cell lymphomas to these two pathways remains controversial. We have previously shown that junctional adhesion molecule C (JAM-C) originally identified at the cell-cell border of endothelial cells, constitutes also a marker of B lymphocytes with a tightly regulated expression during B cell differentiation: immature B cells, GC-B cells and plasma cells stain negatively, whereas mature, memory and marginal zone derived B cells stain strongly positive. Here we test the expression of JAM-C on a series of patients with B cell lymphomas. Methods B lymphocytes from the peripheral blood of 158 untreated patients were analyzed using flow cytometry with standard antibody panels (CD5, CD10, CD11c, CD22, CD23, CD25, CD38, CD103, FMC7, sIg). Diagnosis of a B cell lymphoma was established according to WHO guidelines, using additionally RT-PCR, karyotyping, or FISH, if necessary. Expression of JAM-C was studied by flow cytometry with a polyclonal antibody obtained from a rabbit immunized with the soluble JAM-C molecule. Results MCL, HCL and MZBL with a supposed origin in the marginal zone stained mostly positive, whereas CLL and FL with a supposed origin in the germinal centre showed mostly a negative staining. No correlation was found in CLL between JAM-C expression and staining for ZAP70 or CD38. In 12 cases routine work-up was not able to precisely establish a diagnosis of CLL or MZBL, and CLL or MCL. In these cases the presence of JAM-C was considered a strong argument against a GC-origin of the malignant B cells. Addition of JAM-C to antibodies used in the Matutes score increased the sensitivity and specificity of this score for the diagnosis of CLL. Furthermore, it may help differentiating MZBL from LPL which otherwise display overlapping immunophenotypes. Conclusion JAM-C constitutes a new diagnostic marker for the differential diagnosis of B cell lymphomas, and is particularly useful for the distinction between CLL and LPL (negative staining) on the one hand and mantle cell and marginal zone B cell lymphomas (positive staining) on the other hand. Disclosures: No relevant conflicts of interest to declare.

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Deregulated PAX-5 Transcription From a TranslocatedIgH Promoter in Marginal Zone Lymphoma

Blood ◽

10.1182/blood.v92.10.3865.422k01_3865_3878 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3865-3878 ◽

Cited By ~ 2

Author(s):

Aline M. Morrison ◽

Ulrich Jäger ◽

Andreas Chott ◽

Michael Schebesta ◽

Oskar A. Haas ◽

...

Keyword(s):

Cell Differentiation ◽

B Cell ◽

Marginal Zone ◽

B Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Chain Gene ◽

Splenic Marginal Zone Lymphoma ◽

Derivative Chromosome ◽

B Cell Differentiation ◽

Loss Of Function

The PAX-5 gene codes for the transcription factor BSAP, which is expressed throughout B-cell development. Although loss-of-function mutation in the mouse showed an essential role forPax-5 in early B lymphopoiesis, gain-of-function mutations have implicated the human PAX-5 gene in the control of late B-cell differentiation. PAX-5 (on 9p13) has been involved together with the immunoglobulin heavy-chain (IgH) gene (on 14q32) in the recurring t(9;14)(p13;q32) translocation that is characteristic of small lymphocytic lymphoma with plasmacytoid differentiation. Here we have characterized a complex t(2;9;14)(p12;p13;q32) translocation present in a closely related non-Hodgkin’s lymphoma referred to as splenic marginal zone lymphoma (MZL). In this MZL-1 translocation, the two promoters of PAX-5 were replaced on the derivative chromosome 14 by an immunoglobulin switch Sμ promoter that was linked to the structural PAX-5 gene upstream of its translation initiation codon in exon 1B. Expression analyses confirmed thatPAX-5 transcription was upregulated due to efficient initiation at the Sμ promoter in the malignant B lymphocytes of patient MZL-1. For comparison we have analyzed PAX-5 expression in another B-cell lymphoma, KIS-1, indicating that transcription from the distalPAX-5 promoter was increased in this tumor in agreement with the previously characterized translocation of the immunoglobulin Eμ enhancer adjacent to PAX-5 exon 1A. In both lymphomas, the J-chain gene, which is thought to be under negative control by BSAP, was not expressed, whereas transcription of the putative target genep53 was unaffected by PAX-5 overexpression. Together these data indicate that the t(9;14)(p13;q32) translocation contributes to lymphoma formation as a regulatory mutation that leads to increasedPAX-5 expression in late B-cell differentiation due to promoter replacement or enhancer insertion.

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CD19-independent instruction of murine marginal zone B-cell development by constitutive Notch2 signaling

Blood ◽

10.1182/blood-2010-12-325944 ◽

2011 ◽

Vol 118 (24) ◽

pp. 6321-6331 ◽

Cited By ~ 39

Author(s):

Franziska Hampel ◽

Stefanie Ehrenberg ◽

Caroline Hojer ◽

Anne Draeseke ◽

Gabriele Marschall-Schröter ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Marginal Zone ◽

Developmental Stages ◽

Cell Lineage ◽

Cell Generation ◽

Specific Gene ◽

B Cell Differentiation ◽

Conditional Expression

Abstract B cell–specific gene ablation of Notch2 results in the loss of the marginal zone (MZ) B-cell lineage. To analyze the effects of constitutive Notch2 signaling in B cells, we have generated a transgenic mouse strain that allows the conditional expression of a constitutively active, intracellular form of Notch2 (Notch2IC). Expression of Notch2IC at the earliest developmental stages of the B-cell lineage completely abolished B-cell generation and led to the development of ectopic T cells in the bone marrow (BM), showing that Notch2IC is acting redundantly with Notch1IC in driving ectopic T-cell differentiation. In B cells clearly committed to the B-cell lineage induction of Notch2IC drove all cells toward the MZ B-cell compartment at the expense of follicular B cells. Notch2IC-expressing B cells reflected the phenotype of wild-type MZ B cells for their localization in the MZ, the expression of characteristic surface markers, their enhanced proliferation after stimulation, and increased basal activity of Akt, Erk, and Jnk. Notch2IC-driven MZ B-cell generation in the spleen was achieved even in the absence of CD19. Our results implicate that a constitutive Notch2 signal in transitional type 1 B cells is sufficient to drive MZ B-cell differentiation.

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