scholarly journals Activation-Induced Cytidine Deaminase Acts as a Mutator in BCR-ABL1-Transformed Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 640-640
Author(s):  
Niklas Feldhahn ◽  
Florian Klein ◽  
Wolf-Karsten Hofmann ◽  
Janet D. Rowley ◽  
Hassan Jumaa ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cells ◽  
Germinal Center ◽  
Somatic Mutations ◽  
Kinase Activity ◽  
Somatic Hypermutation ◽  
Lymphoblastic Leukemia ◽  
V Region ◽  
Germinal Center B Cells

Abstract Acute lymphoblastic leukemia (ALL) cells are derived from B and T cell precursors and typically carry rearranged immunglobulin (Ig) or T cell receptor (TCR) variable (V) region genes devoid of somatic mutations. The Philadelphia chromsome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Here we show that oncogenic BCR-ABL1 kinase activity induces aberrant somatic hypermutation in Ph-positive ALL cells. Under physiological conditions, somatic hypermutation is restricted to mature germinal center B cells and depends on expression of the DNA-deaminating enzyme AID. Comparing Ph-positive and Ph-negative ALL cells, AID expression was found in 24 of 28 Ph-positive but only 3 of 80 Ph-negative ALLs. As shown by RT-PCR and Western blot, expression of AID in Ph-positive ALL cells reached similar levels as in germinal center B cells. Forced expression of BCR-ABL1 in Ph-negative ALL cells and usage of the BCR-ABL1-kinase inhibitor STI571 revealed that BCR-ABL1 kinase activity is required and sufficient to induce aberrant expression of AID in Ph-positive ALL. Consistent with aberrant AID expression in Ph-positive ALL, Ig VH region genes were mutated in most Ph-positive but unmutated in Ph-negative cases. Of note, also non-Ig genes including BCL6 and MYC harbored somatic mutations in Ph-positive but not Ph-negative ALL cells. Likewise, Ph-positive T cell lineage ALL cells express AID and carry somatically mutated TCRβ V region genes. As demonstrated by ligation-mediated PCR, AID introduced DNA-single-strand breaks also within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to both inhibition of BCR-ABL1 kinase activity and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset.

scholarly journals The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis

Immunity ◽  
2019 ◽  
Vol 51 (2) ◽  
pp. 310-323.e7 ◽  
Author(s):  
Michelle A. Mintz ◽  
James H. Felce ◽  
Marissa Y. Chou ◽  
Viveka Mayya ◽  
Ying Xu ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Germinal Center ◽  
A Cell ◽  
T Cell Help ◽  
Germinal Center B Cells

Analysis of IgVH, BCL-6, PIM, RHO/TTF and PAX5 Mutational Status in Splenic and Nodal Marginal Zone B Cell Lymphoma Suggests a Particular B Cell Origin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 162-162 ◽  
Author(s):  
Alexandra Traverse-Glehen ◽  
Aurelie Verney ◽  
Lucille Baseggio ◽  
Pascale Felman ◽  
Evelyne Callet-Bauchu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Mutations ◽  
Marginal Zone ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Marginal Zone B Cells ◽  
Mutational Status ◽  
Frequent Absence

Abstract Background and Objectives Splenic and nodal marginal zone B cell lymphoma (SMZL and NMZL) have been recently identified as distinct clinicopathological entities in the WHO classification. These lymphomas entities may have a common origin in the marginal B-cell compartment of the lymphoid organs. However the precise cell of origin of marginal zone B cells, its status in the B cell differentiation pathway and the mechanisms involved in lymphomagenesis remain unclear. The most widely held view is that marginal zone B cells are mostly memory B cells. But the origin of these cells, especially the transit through germinal center pathway, remains contradictory. Somatically mutated variable-region of immunoglobulin genes and bcl-6 gene represent at this time faithful markers for exposure to the germinal center. In addition, aberrant somatic hypermutations have been suggested to contribute to the development of B-cell lymphomas, occurring in the 5′ sequence of several proto-oncogenes. Interestingly those mutation do not occur in normal germinal center B cells. Design and Methods: IgVH, BCL-6, PIM1, Rho/TTF and PAX 5 genes, highly mutated in DLBCL and other indolent lymphoma such as B-CLL, were analysed for the presence of somatic mutations from 50 marginal zone lymphoma tissue and blood samples (21 NMZL and 29 SMZL including 10 cases with numerous villous lymphoma cells in peripheral blood). According to the morphological and immunophenotypical analysis, the fraction of malignant cells in the specimen was 70% or more in all cases. Mutational analysis was restricted to the regions previously shown to contain more than 95% of mutations in DLBCL. PCR products were directly sequenced on both sides and perfomed in duplicate in two independent reactions. Results: Out of 18 NMZL cases analysed for IgVH mutational status (3 cases not analysed for IgVH) 15 cases were mutated and 21 out of 28 in SMZL cases. Mutation of BCL-6 was detected in only 1 NMZL patients (1/21) and 1 SMZL patients (1/29). For RhoH/TTF, PIM1, PAX5 the mutation average was also low with only 1 case mutated per group and per gene, with a different case mutated in each for each gene. Conclusion In summary, we demonstrate the low frequency of aberrant somatic mutations in SMZL and NMZL, suggesting that this process is probably not a major contributor to lymphomageneis. However the frequent absence of mutation in BCL6 suggest a particular differentiation pathway, as suggested before in normal marginal zone B cells, possibly without transit through the germinal center. Interestingly the relatively high frequency of VH mutated cases compared with the frequent absence of mutation of BCL6, considered as a specific germinal center tag, could suggest somatic hypermutation outside the germinal center. In addition the absence of hypermutation could be linked with the absence of recurrent translocation in SMZL and NMZL, the translocation process haveing been associated with somatic hypermutation dysfunction.

Nonimmunoglobulin Gene Hypermutation in Germinal Center B Cells

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2167-2172 ◽  
Author(s):  
Huai-Zheng Peng ◽  
Ming-Qing Du ◽  
Athanasios Koulis ◽  
Antonella Aiello ◽  
Ahmet Dogan ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Mantle Zone ◽  
Germinal Center Reaction ◽  
Inherent Feature ◽  
Mantle Cell ◽  
Center Cell ◽  
Germinal Center B Cells

Somatic hypermutation is the most critical mechanism underlying the diversification of Ig genes. Although mutation occurs specifically in B cells during the germinal center reaction, it remains a matter of debate whether the mutation machinery also targets non-Ig genes. We have studied mutations in the 5′ noncoding region of the Bcl6 gene in different subtypes of lymphomas. We found frequent hypermutation in follicular lymphoma (25 of 59 = 42%) (germinal center cell origin) and mucosa-associated lymphoid tissue (MALT) lymphoma (19 of 45 = 42%) (postgerminal center), but only occasionally in mantle cell lymphoma (1 of 21 = 4.8%) (pregerminal center). Most mutations were outside the motifs potentially important for transcription, suggesting they were not important in lymphomagenesis but may, like Ig mutation, represent an inherent feature of the lymphoma precursor cells. Therefore, we investigated their normal cell counterparts microdissected from a reactive tonsil. Bcl6 mutation was found in 13 of 24 (54%) clones from the germinal centre but only in 1 of 24 (4%) clones from the naive B cells of the mantle zone. The frequency, distribution, and nature of these mutations were similar to those resulting from the Ig hypermutation process. The results show unequivocal evidence of non-Ig gene hypermutation in germinal center B cells and provide fresh insights into the process of hypermutation and lymphomagenesis.

scholarly journals M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4849-4856 ◽  
Author(s):  
Dominik Schenten ◽  
Angela Egert ◽  
Manolis Pasparakis ◽  
Klaus Rajewsky
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Gene Expression Signature ◽  
Antibody Responses ◽  
B Cell Lymphomas ◽  
Clinical Prognosis ◽  
V Region

AbstractIn T-cell–dependent antibody responses, antigen-specific B cells undergo a phase of secondary antibody diversification in germinal centers (GCs). Somatic hypermutation (SHM) introduces mutations into the rearranged immunoglobulin (Ig) variable (V) region genes, and class-switch recombination (CSR) alters the Ig heavy (H) chain constant region. Aberrant SHM or CSR is thought to contribute to the development of GC-derived B-cell malignancies. Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of such GC-derived tumors. Based on their gene expression profile, DLBCLs can be divided into activated B-cell–like and GC-like subgroups. The human gene HGAL is predominantly expressed in GCs. It is also part of the gene expression signature of GC-like DLBCL, and its high expression in DLBCL has been associated with a better clinical prognosis. We have generated mice deficient of the HGAL homologue M17 in order to investigate its functional significance. The mutant animals form normal GCs, undergo efficient CSR and SHM, and mount T-cell–dependent antibody responses similar to wild-type controls. Thus, M17 is dispensable for the GC reaction, and its potential function in the pathogenesis of DLBCL remains elusive.

scholarly journals T cell help controls the speed of the cell cycle in germinal center B cells

Science ◽  
2015 ◽  
Vol 349 (6248) ◽  
pp. 643-646 ◽  
Author(s):  
A. D. Gitlin ◽  
C. T. Mayer ◽  
T. Y. Oliveira ◽  
Z. Shulman ◽  
M. J. K. Jones ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
B Cells ◽  
Germinal Center ◽  
T Cell Help ◽  
Germinal Center B Cells

Promotion and maintenance of leukemia by ERG

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3858-3868 ◽  
Author(s):  
Shinobu Tsuzuki ◽  
Osamu Taguchi ◽  
Masao Seto
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Chromosome 21 ◽  
Human Leukemia ◽  
General Role ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Adult Leukemia

Abstract The Ets-related gene (ERG) located on human chromosome 21 encodes a transcription factor and is thought to be causally related to Down syndrome–associated acute megakaryocytic leukemia in childhood. In clinical adult leukemia, however, increased expression of ERG is indicative of poor prognosis in T-cell acute lymphoblastic leukemia and cytogenetically normal acute myeloid leukemia, although the involvement of ERG in the development of adult leukemia remains elusive. Here, we show that forced expression of ERG in adult BM cells alters differentiation and induces expansion of T and erythroid cells and increases frequencies of myeloid progenitors in mouse BM transplantation models. The expanded T cells then develop T-cell acute lymphoblastic leukemia after acquisition of mutations in the Notch1 gene. Targeted expression of ERG into B cells also altered differentiation and promoted growth of precursor B cells. Overall, these findings suggest a general role of ERG in promoting growth of adult hematopoietic cells in various lineages. In line with this, shRNA-mediated silencing of ERG expression attenuated growth of human leukemia cell lines of various lineages. Thus, ERG is capable of promoting the development of leukemia and is crucial for its maintenance.

scholarly journals WASp Is Crucial for the Unique Architecture of the Immunological Synapse in Germinal Center B-Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanan Li ◽  
Anshuman Bhanja ◽  
Arpita Upadhyaya ◽  
Xiaodong Zhao ◽  
Wenxia Song
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lipid Bilayers ◽  
Germinal Center ◽  
Actin Polymerization ◽  
Immunological Synapse ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Membrane Protrusions ◽  
Germinal Center B Cells

B-cells undergo somatic hypermutation and affinity maturation in germinal centers. Somatic hypermutated germinal center B-cells (GCBs) compete to engage with and capture antigens on follicular dendritic cells. Recent studies show that when encountering membrane antigens, GCBs generate actin-rich pod-like structures with B-cell receptor (BCR) microclusters to facilitate affinity discrimination. While deficiencies in actin regulators, including the Wiskott-Aldrich syndrome protein (WASp), cause B-cell affinity maturation defects, the mechanism by which actin regulates BCR signaling in GBCs is not fully understood. Using WASp knockout (WKO) mice that express Lifeact-GFP and live-cell total internal reflection fluorescence imaging, this study examined the role of WASp-mediated branched actin polymerization in the GCB immunological synapse. After rapid spreading on antigen-coated planar lipid bilayers, GCBs formed microclusters of phosphorylated BCRs and proximal signaling molecules at the center and the outer edge of the contact zone. The centralized signaling clusters localized at actin-rich GCB membrane protrusions. WKO reduced the centralized micro-signaling clusters by decreasing the number and stability of F-actin foci supporting GCB membrane protrusions. The actin structures that support the spreading membrane also appeared less frequently and regularly in WKO than in WT GCBs, which led to reductions in both the level and rate of GCB spreading and antigen gathering. Our results reveal essential roles for WASp in the generation and maintenance of unique structures for GCB immunological synapses.

scholarly journals In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells.

1993 ◽  
Vol 178 (4) ◽  
pp. 1293-1307 ◽  
Author(s):  
J Jacob ◽  
J Przylepa ◽  
C Miller ◽  
G Kelsoe
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Point Mutations ◽  
Variable Region ◽  
Germinal Centers ◽  
Primary Immune Response ◽  
Kinetics Of ◽  
Mutation And Selection ◽  
Germinal Center B Cells

In the murine spleen, germinal centers are the anatomic sites for antigen-driven hypermutation and selection of immunoglobulin (Ig) genes. To detail the kinetics of Ig mutation and selection, 178 VDJ sequences from 16 antigen-induced germinal centers were analyzed. Although germinal centers appeared by day 4, mutation was not observed in germinal center B cells until day 8 postimmunization; thereafter, point mutations favoring asymmetrical transversions accumulated until day 14. During this period, strong phenotypic selection on the mutant B lymphocytes was inferred from progressively biased distributions of mutations within the Ig variable region, the loss of crippling mutations, decreased relative clonal diversity, and increasingly restricted use of canonical gene segments. The period of most intense selection on germinal center B cell populations preceded significant levels of mutation and may represent a physiologically determined restriction on B cells permitted to enter the memory pathway. Noncanonical Ig genes recovered from germinal centers were mostly unmutated although they probably came from antigen-reactive cells. Together, these observations demonstrate that the germinal center microenvironment is rich and temporally complex but may not be constitutive for somatic hypermutation.

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