scholarly journals PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma

2021 ◽  
Author(s):  
Annalisa D'Avola ◽  
Nathalie Legrave ◽  
Mylene Tajan ◽  
Probir Chakravarty ◽  
Ryan Shearer ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
Cellular Proliferation ◽  
B Cell Lymphoma ◽  
B Cell Activation ◽  
Germinal Center Reaction ◽  
Germinal Center B Cell

The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B-cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate limiting enzyme in this pathway, leads to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis is a characteristic of germinal center B-cell derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induces apoptosis in lymphoma cells reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.

scholarly journals Prediction and characterization of diffuse large B-cell lymphoma cell-of-origin subtypes using targeted sequencing

2021 ◽  
Author(s):  
Sally E Trabucco ◽  
Ethan S Sokol ◽  
Sophia L Maund ◽  
Jay A Moore ◽  
Garrett M Frampton ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
B Cell Lymphoma ◽  
B Cell Activation ◽  
Cell Of Origin ◽  
Sequencing Platform ◽  
Germinal Center B Cell ◽  
Putative Origin ◽  
Comprehensive Genomic Profiling

The aim of the present study was to determine cell of origin (COO) from a platform using a DNA-based method, COO DNA classifier (COODC). A targeted exome-sequencing platform that applies the mutational profile of a sample was used to classify COO subtype. Two major mutational signatures associated with COO were identified: Catalogue of Somatic Mutations in Cancer (COSMIC) signature 23 enriched in activated B-cell (ABC) and COSMIC signature 3, which suggested increased frequency in germinal center B-cell (GCB). Differential mutation signatures linked oncogenesis to mutational processes during B-cell activation, confirming the putative origin of GCB and ABC subtypes. Integrating COO with comprehensive genomic profiling enabled identification of features associated with COO and demonstrated the feasibility of determining COO without RNA.

scholarly journals Lymphoma models for B cell activation and tolerance. X. Anti-mu-mediated growth arrest and apoptosis of murine B cell lymphomas is prevented by the stabilization of myc.

1994 ◽  
Vol 179 (1) ◽  
pp. 221-228 ◽  
Author(s):  
G Fischer ◽  
S C Kent ◽  
L Joseph ◽  
D R Green ◽  
D W Scott
Keyword(s):  
Growth Inhibition ◽  
B Cell ◽  
Antisense Oligonucleotides ◽  
Growth Regulation ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
B Cell Activation ◽  
Tgf Beta ◽  
B Cell Lymphomas

Treatment of the WEHI-2131 or CH31 B cell lymphomas with anti-mu or transforming growth factor (TGF)-beta leads to growth inhibition and subsequent cell death via apoptosis. Since anti-mu stimulates a transient increase in c-myc and c-fos transcription in these lymphomas, we examined the role of these proteins in growth regulation using antisense oligonucleotides. Herein, we demonstrate that antisense oligonucleotides for c-myc prevent both anti-mu- and TGF-beta-mediated growth inhibition in the CH31 and WEHI-231 B cell lymphomas, whereas antisense c-fos has no effect. Furthermore, antisense c-myc promotes the appearance of phosphorylated retinoblastoma protein in the presence of anti-mu and prevents the progression to apoptosis as measured by propidium iodide staining. Northern and Western analyses show that c-myc message and the levels of multiple myc proteins were maintained in the presence of antisense c-myc, results indicating that myc species are critical for the continuation of proliferation and the prevention of apoptosis. These data implicate c-myc in the negative signaling pathway of both TGF-beta and anti-mu.

scholarly journals Germinal center B cell development has distinctly regulated stages completed by disengagement from T cell help

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ting-ting Zhang ◽  
David G Gonzalez ◽  
Christine M Cote ◽  
Steven M Kerfoot ◽  
Shaoli Deng ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
B Cell Differentiation ◽  
B Cell Maturation ◽  
Germinal Center B Cell ◽  
T Cell Help ◽  
Dose Dependent

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.

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