Activation Induced Cytidine Deaminase (AID) Is Required for Germinal-Center Derived Lymphomagenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 223-223
Author(s):  
Laura Pasqualucci ◽  
Mara Compagno ◽  
Tongwei Mo ◽  
Paula Smith ◽  
Herbert C. Morse ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Profile Analysis ◽  
Cytidine Deaminase ◽  
Receptor Gene ◽  
Activation Induced Cytidine Deaminase ◽  
Hodgkin's Lymphomas

Abstract Most B cell non-Hodgkin’s lymphomas (B-NHL) derive from germinal center (GC) B cells and their pathogenesis is associated with the accumulation of distinct genetic lesions, including chromosomal translocations and a more recently identified mechanism of genomic instability, termed aberrant somatic hypermutation. These alterations are thought to be due to mistakes occurring during two GC-associated immunoglobulin (Ig) genes remodeling processes: class switch recombination (CSR) and somatic hypermutation (SHM). However, this model has never been formally proven. To conclusively investigate the role of CSR and SHM in the pathogenesis of B-NHL, we examined whether lymphoma development in mice requires the function of activation induced cytidine deaminase (AID), a DNA editing enzyme expressed specifically in GC and activated B cells and essential for both processes. Three transgenic mouse models were generated by crossing lymphoma-prone mice (λMYC, λMYC/IμHABCL6 and IμHABCL6) with mice (AID−/−) that are unable to undergo both SHM and CSR. The λMYC mice develop a diffusely infiltrating monoclonal proliferation of pre-GC origin, with unmutated IgV genes and lack of BCL6 expression, and therefore presumably independent from AID-associated DNA remodeling events. Conversely, lymphomas in λMYC/IμHABCL6 and IμHABCL6 mice recapitulate GC/post GC-derived malignancies, in that the former display somatically mutated IgV genes and upregulation of post-GC markers (CD138) in most of the cases, while the latter develop a splenic lymphoproliferative syndrome that culminates, past 12 months of age, in clonal B cell lymphomas with DLBCL morphology and somatically mutated IgV genes (~70% of the animals) (Cattoretti et al., Cancer Cell 7:445–455, 2005). Mice were monitored for tumor incidence and survival, and a combination of histologic, immunophenotypic and gene expression profiling analysis was used for tumor characterization. As expected, no significant differences in event-free survival and lymphoma type were observed between AID-proficient and AID-deficient λMYC mice, in agreement with their pre-GC derivation. Conversely, a phenotypic shift of the tumor was observed in λMYC/IμHABCL6 mice when bred into an AID−/− background, with >80% of the cases (N=21/26) reverting to a pre-GC phenotype (loss of GC/post GC markers) undistinguishable from that of the λMYC and λMYC/AID−/− mice. Gene expression profile analysis on representative cases (N=10 λMYC/IμHABCL6 and 5 each for λMYC, λMYC/AIDKO, λMYC/IμHABCL6/AIDKO) confirmed significant phenotypic similarities between pre-GC derived λMYC lymphomas and the λMYC/IμHABCL6/AID −/− lymphomas, which co-segregated in a separate cluster from λMYC/IμHABCL6 tumors. Analogously, a significant reduction in DLBCL frequency was observed in the IμHABCL6/AIDKO cohort as compared to IμHABCL6 mice (N= 4/19, 21% vs 8/14, 57%; p=0.03). Taken together, these results indicate that GC-derived lymphomas cannot develop in the absence of AID, thereby providing direct support to the notion that AID-mediated mistakes in antigen receptor gene modification events (CSR and SHM) represent major contributors to B-NHL pathogenesis.

scholarly journals miR-181b negatively regulates activation-induced cytidine deaminase in B cells

2008 ◽  
Vol 205 (10) ◽  
pp. 2199-2206 ◽  
Author(s):  
Virginia G. de Yébenes ◽  
Laura Belver ◽  
David G. Pisano ◽  
Susana González ◽  
Aranzazu Villasante ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Bystander Effect ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Fine Tuning ◽  
Functional Screening ◽  
Activation Induced Cytidine Deaminase ◽  
Activated B Cells

Activated B cells reshape their primary antibody repertoire after antigen encounter by two molecular mechanisms: somatic hypermutation (SHM) and class switch recombination (CSR). SHM and CSR are initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues on the immunoglobulin loci, which leads to the generation of DNA mutations or double-strand break intermediates. As a bystander effect, endogenous AID levels can also promote the generation of chromosome translocations, suggesting that the fine tuning of AID expression may be critical to restrict B cell lymphomagenesis. To determine whether microRNAs (miRNAs) play a role in the regulation of AID expression, we performed a functional screening of an miRNA library and identified miRNAs that regulate CSR. One such miRNA, miR-181b, impairs CSR when expressed in activated B cells, and results in the down-regulation of AID mRNA and protein levels. We found that the AID 3′ untranslated region contains multiple putative binding sequences for miR-181b and that these sequences can be directly targeted by miR-181b. Overall, our results provide evidence for a new regulatory mechanism that restricts AID activity and can therefore be relevant to prevent B cell malignant transformation.

Expression of a Dysfunctional Activation Induced Cytidine Deaminase Is Correlated with Disease Progression in Splenic Marginal Zone Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2397-2397
Author(s):  
Gabriel Brisou ◽  
Laurent Jallades ◽  
Alexandra Traverse-Glehen ◽  
Francoise Berger ◽  
Aurélie Verney ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Marginal Zone ◽  
Cytidine Deaminase ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Marginal Zone B Cells ◽  
Activation Induced Cytidine Deaminase ◽  
Splicing Variants

Abstract Abstract 2397 B cells can undergo at least two differentiation pathways, dependent of T cells or not, starting from follicular or marginal zone B cells respectively. The T-independent response, less understood than the germinal center reaction, is triggered by specific antigens and arises from marginal zone B cells. During this development, some B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR), triggered by the same DNA editing enzyme called Activation Induced Cytidine Deaminase (AID). The splenic marginal zone lymphoma (SMZL) is a rare lymphoproliferative disorder characterized by a clonal expansion of B cells in the marginal zone of the spleen. These B-cells underwent SHM in roughly 60% of the cases but nearly none underwent CSR. These observations suggest that tumor clones originate from a particular activated B cell subset not transiting through the germinal center. In order to confirm this hypothesis, we focused our work on the status and impact of AID in this disease and worked on purified B cells extracted from spleen of well-characterized SMZL cases. We determined AID status by quantitative RT-PCR analysis on 27 SMZL samples and compared it with 5 controls. In the SMZL group the relative level of expression of AID is heterogeneous but two subgroups could be distinguished: one considered as expressing AID (14 cases out of the 27 analyzed), the remaining considered as not expressing AID. When we compared AID expression rate with occurrence of SHM and CSR, no clear correlation between AID expression and presence of SHM or CSR could be observed suggesting that AID, when expressed, is dysfunctional. To address this hypothesis, we first analyzed AID protein by immunohistochemistry and a good correlation between IHC signal and AID mRNA expression level has been observed. As AID gene was not mutated, we next focused our work on AID mRNA splicing variants as these variants exhibit different functions according to the domain of the protein they contain in a murine model. We found that SMZL B cells express various splicing variants of AID mRNA, some of those variants corresponding to the full length isoform (n = 6/17), and other variants corresponding to AID-ΔE4a (n = 2/17) or AID-ΔE4 (n = 7/17) isoforms known to be expressed in normal germinal center B cells as well as in Chronic Lymphocytic and Acute Lymphoblastic Leukemia. These findings indicate that although expressed at the mRNA and protein levels, AID may not be fully functional in SMZL cases. Finally we addressed the potential clinical significance of AID expression. We identified for that purpose a group of “progressive SMZL” patients that had received immuno-chemotherapy after splenectomy because of a significant risk of progression or transformation into aggressive large B cell lymphoma (n = 8/27) pre-empting outcome differences. We found a higher proportion of AID expressing patients in the defined “progressive SMZL” group (n = 7/8) as compared to the proportion found in the “indolent SMZL” group (n = 5/14, p = 0,03). Altogether, this data suggest that the B cell clone leading to SMZL originate from the marginal zone and support the hypothesis of a lymphoproliferative disorder affecting the T-independent response. AID expression in SMZL may reflect an advanced stage of the disease and could be correlated with the evolution of the lymphoma into a more clinically or pathologically aggressive form. Disclosures: No relevant conflicts of interest to declare.

Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution of BCR-ABL1-Driven B Cell Lineage Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 181-181
Author(s):  
Tanja Gruber ◽  
Mi Sook Chang ◽  
Richard Sposto ◽  
Markus Müschen
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
B Cell ◽  
Genetic Instability ◽  
Tumor Suppressor Genes ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Activation Induced Cytidine Deaminase

Abstract Abstract 181 Activation-Induced Cytidine Deaminase (AID) is required for somatic hypermutation and immunoglobulin (Ig) class switch recombination in germinal center (GC) B cells. Occasionally, AID can target non-Ig genes and thereby promote GC B cell lymphomagenesis. We recently demonstrated that the oncogenic BCR-ABL1 kinase induces aberrant expression of AID in pre-B acute lymphoblastic leukemia (ALL). Compared to other ALL subtypes, BCR-ABL1 ALL is considered high risk and is characterized by a high degree of genetic instability. Because aberrant mutational activity of AID is associated with malignant transformation in B cell lymphoma, we sought to determine whether aberrant AID expression contributes to clonal evolution and genetic instability in Ph+ ALL. To investigate the function of AID expression in Ph+ ALL, we established a genetic loss-of-function model for Ph+ ALL: Bone marrow cells from AID−/− mice and AID+/+ controls were transformed by retroviral transduction with BCR-ABL1 under B lymphoid culture conditions and subsequently injected into lethally irradiated congenic recipients. Mice transplanted with AID−/−BCR-ABL1 ALL had prolonged median survival as compared to mice transplanted with leukemia cells generated from AID+/+ bone marrow (AID−/− 34 days (n=18) vs AID+/+ 13 days (n=21); p<0.0001). In secondary and tertiary transplant experiments, however, the difference between AID−/− and AID+/+BCR-ABL1 ALL narrowed as determined by a decreasing hazard ratio (from 25.5 in the primary transplant to 5.1 in the secondary and 2.9 in the tertiary transplantation). These findings suggest that aberrant AID expression accelerates clonal evolution of Ph+ ALL, but AID-independent factors exist that are sufficient for transformation. In support of enzymatic activity of AID in BCR-ABL1-transformed ALL cells, we observed that aberrant somatic hypermutation of non-immunoglobulin genes in these leukemias was largely dependent on AID: mutations in the known hypermutation target genes Pax5 and Rhoh were increased in AID+/+ but not AID−/−BCR-ABL1 ALL cells. Mutations in the first intron of Rhoh as observed here are relevant because they interfere with Rhoh transcription. Indeed, we found that Rhoh mRNA levels are significantly higher in AID−/− compared to AID+/+BCR-ABL1 ALL cells. Rhoh is a hematopoietic specific GTPase that negatively regulates Rac-mediated signaling downstream of the oncogenic BCR-ABL1 kinase. AID-dependent mutation and transcriptional inactivation of Rhoh in BCR-ABL1 ALL therefore likely augments oncogenic BCR-ABL1 signaling. Consistent with a causative role of AID in genetic instability, AID−/− leukemia had a lower frequency of amplifications (17+2 vs 45+7; p=0.002) and deletions (11+2 vs 40+7; p=0.003) as compared to AID+/+ leukemias. AID−/− and AID+/+ ALL cells showed a markedly distinct gene expression pattern with 2,365 differentially expressed genes (p=0.003; FDR 0.05). A detailed analysis of these differences in gene expression revealed that AID−/−BCR-ABL1 ALL cells failed to downregulate a number of tumor suppressor genes including p53, Rhoh, Cdkn1a (p21), and Blnk (SLP65). AID-dependent downregulation of p53 in BCR-ABL1 ALL cells is of particular importance, because previous work demonstrated that transcriptional repression of p53 in normal GC B cells is required to make these cells permissive to high levels of AID expression. AID-induced DNA damage would otherwise activate p53 and rapidly induce apoptosis. Compared to AID-deficient BCR-ABL1 ALL, AID+/+BCR-ABL1 ALL cells are more resistant to Imatinib-treatment. However, acquisition of BCR-ABL1 kinase domain mutations does not appear to be the main cause of drug-resistance in this experiment, since only one relevant mutation was amplified from AID+/+ ALL cells (no mutations in AID−/− ALL cells). We conclude that AID accelerates clonal evolution in BCR-ABL1 ALL by enhancing genetic instability, aberrant somatic hypermutation, and by negative regulation of tumor suppressor genes. Disclosures: No relevant conflicts of interest to declare.

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 547-554 ◽  
Author(s):  
Ahmad Zaheen ◽  
Bryant Boulianne ◽  
Jahan-Yar Parsa ◽  
Shaliny Ramachandran ◽  
Jennifer L. Gommerman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cytidine Deaminase ◽  
Enzyme Activation ◽  
Specific Enzyme ◽  
Tissue Microenvironment ◽  
Activation Induced Cytidine Deaminase ◽  
Immunoglobulin Locus

Abstract The germinal center (GC) is a transient lymphoid tissue microenvironment that fosters T cell–dependent humoral immunity. Within the GC, the B cell–specific enzyme, activation-induced cytidine deaminase (AID), mutates the immunoglobulin locus, thereby altering binding affinity for antigen. In the absence of AID, larger GC structures are observed in both humans and mice, but the reason for this phenomenon is unclear. Because significant apoptosis occurs within the GC niche to cull cells that have acquired nonproductive mutations, we have examined whether a defect in apoptosis could account for the larger GC structures in the absence of AID. In this report, we reveal significantly reduced death of B cells in AID−/− mice as well as in B cells derived from AID−/− bone marrow in mixed bone marrow chimeric mice. Furthermore, AID-expressing B cells show decreased proliferation and survival compared with AID−/− B cells, indicating an AID-mediated effect on cellular viability. The GC is an etiologic site for B-cell autoimmunity and lymphomagenesis, both of which have been linked to aberrant AID activity. We report a link between AID-induced DNA damage and B-cell apoptosis that has implications for the development of B-cell disorders.

scholarly journals A novel human B cell subpopulation representing the initial germinal center population to express AID

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2545-2552 ◽  
Author(s):  
Grant R. Kolar ◽  
Darshna Mehta ◽  
Rosana Pelayo ◽  
J. Donald Capra
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Cell Subpopulation ◽  
Human Tonsil ◽  
Germinal Center Reaction ◽  
Cell Subpopulations ◽  
Human B Cell

Abstract We have identified a novel mature human B-cell subpopulation in the human tonsil that has characteristics of both naive B cells and germinal center B cells including the expression of activation-induced cytidine deaminase (AID), which is essential for the process of immunoglobulin somatic hypermutation and class-switch recombination. These cells are clearly somatically hypermutated, albeit modestly. Their phenotype (IgD+CD38−CD23−FSChiCD71+) is unique and suggests they may be intermediate between both naive and germinal center cells. Morphologically they are also distinct from other B-cell subpopulations. The evidence presented suggests these cells may be the founder cells of the germinal center reaction (a pro-GC cell) and may be the normal counterpart of the mantle cell lymphoma cell.

Expression of the AID protein in normal and neoplastic B cells

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3318-3325 ◽  
Author(s):  
Laura Pasqualucci ◽  
Roberta Guglielmino ◽  
Jane Houldsworth ◽  
Jessica Mohr ◽  
Said Aoufouchi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Variable Region ◽  
Affinity Maturation ◽  
Lymphocytic Leukemia ◽  
Antibody Affinity ◽  
Disease Subtype ◽  
Activation Induced Cytidine Deaminase

Abstract Somatic hypermutation (SHM) targets primarily the immunoglobulin variable region (IgV) genes in germinal center (GC) B cells, thereby allowing antibody affinity maturation. A malfunction of SHM, termed aberrant somatic hypermutation (ASHM), was found in about 50% of diffuse large B-cell lymphomas (DLBCLs), leading to mutations in the 5′ sequences of multiple genes, including oncogenes. Although the SHM mechanism is largely unknown, it was shown to require the activation-induced cytidine deaminase (AID) gene. AID mRNA is expressed in GC B cells and GC-derived lymphomas, but the pattern of expression of the AID protein is not known. Using 2 specific antibodies, here we show that the AID protein can be detected in GC centroblasts and their transformed counterpart (Burkitt lymphoma) but not in pre-GC B cells and post-GC neoplasms, including B-cell chronic lymphocytic leukemia and multiple myeloma. DLBCLs displayed variable levels of AID expression, which did not correlate with IgV ongoing hypermutation, ASHM, or disease subtype. Finally, both in normal and malignant B cells the AID protein appeared predominantly localized in the cytoplasm. These results indicate that the AID protein is specifically expressed in normal and transformed GC B cells; nonetheless, its predominantly cytoplasmic localization suggests that additional mechanisms may regulate its function and may be altered during lymphomagenesis. (Blood. 2004;104:3318-3325)

scholarly journals CD45RO enriches for activated, highly mutated human germinal center B cells

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3917-3925 ◽  
Author(s):  
Stephen M. Jackson ◽  
Natessa Harp ◽  
Darshna Patel ◽  
Jeffrey Zhang ◽  
Savannah Willson ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Somatic Mutation ◽  
Germinal Center ◽  
Cytidine Deaminase ◽  
Annexin V ◽  
Cell Development ◽  
B Cell Development ◽  
Activation Induced Cytidine Deaminase

Abstract To date, there is no consensus regarding the influence of different CD45 isoforms during peripheral B-cell development. Examining correlations between surface CD45RO expression and various physiologic processes ongoing during the germinal center (GC) reaction, we hypothesized that GC B cells, like T cells, that up-regulate surface RO should progressively acquire phenotypes commonly associated with activated, differentiating lymphocytes. GC B cells (IgD−CD38+) were subdivided into 3 surface CD45RO fractions: RO−, RO+/−, and RO+. We show here that the average number of mutations per IgVH transcript increased in direct correlation with surface RO levels. Conjunctional use of RO and CD69 further delineated low/moderately and highly mutated fractions. Activation-induced cytidine deaminase (AID) mRNA was slightly reduced among RO+ GC B cells, suggesting that higher mutation averages are unlikely due to elevated somatic mutation activity. Instead, RO+ GC B cells were negative for Annexin V, comprised mostly (93%) of CD77− centrocytes, and were enriched for CD69+ cells. Collectively, RO+ GC B cells occupy what seems to be a specialized niche comprised mostly of centrocytes that may be in transition between activation states. These findings are among the first to sort GC B cells into populations enriched for live mutated cells solely using a single extracellular marker.

scholarly journals Immunolocalization of the ICE/Ced-3–Family Protease, CPP32 (Caspase-3), in Non-Hodgkin's Lymphomas, Chronic Lymphocytic Leukemias, and Reactive Lymph Nodes

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3817-3825 ◽  
Author(s):  
Stanislaw Krajewski ◽  
Randy D. Gascoyne ◽  
Juan M. Zapata ◽  
Maryla Krajewska ◽  
Shinichi Kitada ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Germinal Center ◽  
Caspase 3 ◽  
Large Cell ◽  
B Cell Lymphomas ◽  
Mantle Zone ◽  
Dynamic Regulation ◽  
Hodgkin's Lymphomas

Immunohistochemical analysis of the apoptosis-effector protease CPP32 (Caspase-3) in normal lymph nodes, tonsils, and nodes affected with reactive hyperplasia (n = 22) showed strong immunoreactivity in the apoptosis-prone germinal center B-lymphocytes of secondary follicles, but little or no reactivity in the surrounding long-lived mantle zone lymphocytes. Immunoblot analysis of fluorescence-activated cell sorted germinal center and mantle zone B cells supported the immunohistochemical results. In 22 of 27 (81%) follicular small cleaved cell non-Hodgkin's B-cell lymphomas, the CPP32-immunopositive germinal center lymphocytes were replaced by CPP32-negative tumor cells. In contrast, the large cell component of follicular mixed cells (FMs) and follicular large cell lymphomas (FLCLs) was strongly CPP32 immunopositive in 12 of 17 (71%) and in 8 of 14 (57%) cases, respectively, whereas the residual small-cleaved cells were poorly stained for CPP32 in all FLCLs and in 12 of 17 (71%) FMs, suggesting that an upregulation of CPP32 immunoreactivity occurred during progression. Similarly, cytosolic immunostaining for CPP32 was present in 10 of 12 (83%) diffuse large cell lymphomas (DLCLs) and 2 of 3 diffuse mixed B-cell lymphomas (DMs). Immunopositivity for CPP32 was also found in the majority of other types of non-Hodgkin's lymphomas studied. Plasmacytomas were CPP32 immunonegative in 4 of 12 (33%) cases, in contrast to normal plasma cells, which uniformly contained intense CPP32 immunoreactivity, implying downregulation of CPP32 in a subset of these malignancies. All 12 peripheral blood B-cell chronic lymphocyte leukemia specimens examined were CPP32 immunopositive, whereas 3 of 3 small lymphocytic lymphomas were CPP32 negative, suggesting that CPP32 expression may vary depending on the tissue compartment in which these neoplastic B cells reside. The results show dynamic regulation of CPP32 expression in normal and malignant lymphocytes.

Mantle cell lymphoma with t(11;14) and unmutated or mutated VH genes expresses AID and undergoes isotype switch events

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2795-2798 ◽  
Author(s):  
Gavin Babbage ◽  
Richard Garand ◽  
Nelly Robillard ◽  
Niklas Zojer ◽  
Freda K. Stevenson ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Tumor Cells ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Activation Induced Cytidine Deaminase ◽  
Mantle Cell ◽  
Vh Genes ◽  
A Minor

Abstract Isotype switch commonly follows onset of somatic hypermutation in the germinal center (GC), with activation-induced cytidine deaminase (AID) as a prerequisite. Mantle cell lymphoma (MCL) with t(11;14) includes a subset with unmutated (UM) and a minor subset with mutated (MUT) VH genes. Here, we investigated whether switch events and AID expression occur in MCL. In 4 of 6 UM and 4 of 7 MUT MCLs, alternative tumor-derived Cγ,α,ϵ transcripts were identified. AID transcripts, including a splice variant, were common to both subsets. AID expression correlated with switch in 8 of 8 cases, but in 3 of 5 cases it occurred with switch absent. Circle transcripts (Iγ-Cμ/Iα-Cμ) were identified in 5 of 7 evaluated cases. In 1 of 12 cases, 12% of tumor cells expressed immunoglobulin L-restricted surface IgA. Ongoing switch recombination events appear to be a feature of MCL, likely restricted to a minor tumor subpopulation, with occasional variant sIg expression. UM MCLs implicate origins from pre-GC B cells and reveal switch events at ectopic sites. (Blood. 2004;103:2795-2798)

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