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

Kolar, Grant R.; Mehta, Darshna; Pelayo, Rosana; Capra, J. Donald

doi:10.1182/blood-2006-07-037150

Cited by 51 publications

(44 citation statements)

References 38 publications

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“…Our observation that AID is predominantly expressed in non-mutated small lymphocytic lymphoma is in line with previous studies on chronic lymphocytic leukemia cells. [15][16][17][18][19] Identical to previous studies on peripheral blood chronic lymphocytic leukemia cells, the V H 1 family member V H 1-69 was also preferentially used in small lymphocytic lymphoma and associated with the non-mutated small lymphocytic lymphoma. 36,37 Similar to Mediterranean countries, we encountered the V H 3-23 family much more frequently than V H 3-21, the prevailing family in Scandinavian countries, which we observed in one single patient.…”

Section: Discussionmentioning

confidence: 99%

“…11 Recent studies on mRNA on fresh material revealed conflicting results concerning the correlation of AID expression and the IgV H mutation status. [15][16][17][18][19] Despite emerging knowledge on molecular alterations influencing the biological behavior of chronic lymphocytic leukemia, it is still not clear from which normal B-cell counterpart malignant chronic lymphocytic leukemia cells evolve. Moreover, there are no data available on the role of molecular alterations in small lymphocytic lymphoma.…”

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AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations

et al. 2010

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The biological behavior of chronic lymphocytic leukemia and small lymphocytic lymphoma is unpredictable. Nonetheless, non-mutated IgV H gene rearrangement, ATM (11q22-23) and p53 (17p13) deletion are recognized as unfavorable prognosticators in chronic lymphocytic leukemia. The mRNA expression of activation-induced cytidine deaminase (AID), an enzyme indispensable for somatic hypermutation processes, was claimed to be predictive of non-mutated chronic lymphocytic leukemia cells in blood. Here, we evaluated AID protein expression compared with known molecular and immunohistochemical prognostic indicators in 71 chronic lymphocytic leukemia/small lymphocytic lymphoma patients using a tissue microarray approach. We found AID heterogeneously expressed in tumor cells as shown by colocalization analysis for CD5 and CD23. Ki-67 positive paraimmunoblasts of the proliferation centers displayed the highest expression. This observation is reflected by a significant association of AID positivity with a high proliferation rate (P ¼ 0.012). ATM deletion was detected in 10% (6/63) of patients and p53 deletion in 19% (13/67) of patients. Moreover, both ATM (P ¼ 0.002) and p53 deletion (P ¼ 0.004) were significantly associated with AID. IgV H gene mutation was seen in 45% (27/60) of patients. Twenty-five percent (17/69) of patients with AID-positive chronic lymphocytic leukemia/small lymphocytic lymphoma displayed a shorter survival than AID-negative chronic lymphocytic leukemia/small lymphocytic lymphoma patients (61 vs 130 months, P ¼ 0.001). Although there was a trend, we could not show an association with the IgV H gene mutation status. Taken together, our study shows that AID expression is an indicator of an unfavorable prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma patients, although it is not a surrogate marker for the IgV H status. Furthermore, the microenvironment of proliferation centers seems to influence AID regulation and might be an initiating factor in its transformation.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations

et al. 2010

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“…As a result, the activationinduced cytidine deaminase (AID) gene is transcribed, which promotes somatic hypermutation and class-switch recombinations. The enzyme was originally defined as specific for GC B cells (20), but this statement was reappraised when AID was detected in the (21) and GC founder cells (22). Simultaneously with AID induction, BR3 expression is lost during the GC traversal (23), and functional inhibition of Pax-5 permits plasma cell (PC) maturation.…”

Section: Cd23mentioning

confidence: 99%

Ectopic Germinal Centers Are Rare in Sjögren’s Syndrome Salivary Glands and Do Not Exclude Autoreactive B Cells

Devauchelle

Fautrel

Daridon

et al. 2009

The Journal of Immunology

142

102

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This study reports on the characterization of B cells of germinal center (GC)-like structures infiltrating the salivary glands (SGs) of patients with Sjögren’s syndrome. Eight two-color combinations were devised to characterize the phenotype of these B cells in 11 SG specimens selected from biopsies obtained from 40 Sjögren’s syndrome patients and three normal tonsils. The 9G4 mAb, which recognizes V4.34-encoded autoAbs, enabled us to identify autoreactive B cells. Quantitative RT-PCR was used to determine the level of mRNAs for activation-induced cytidine deaminase (AICDA), repressors and transcription factors. CD20+IgD−CD38+CD21+CD24− B cells, similar to those identified in tonsil GCs, were seen in the SGs of four patients and, and since they expressed AICDA, they were termed “real GCs”. CD20+IgD+CD38−CD21+CD24+ B cells, seen in aggregates from the remaining seven samples, were characteristically type 2 transitional B cells and marginal zone-type B cells. They lacked AICDA mRNAs and were termed “aggregates”. Real GCs from SGs contained mRNAs for Pax-5 and Bcl-6, like tonsil GC cells, whereas aggregates contained mRNAs for Notch-2, Blimp-1, IRF-4, and BR3, similar to marginal zone B cells. Further experimental data in support of this dichotomy included the restriction of CXCR5 expression to real GC cells, while sphingosine 1-phosphate receptor 1 was expressed only in aggregates. In contrast, both types of B cell clusters expressed the idiotype recognized by the 9G4 mAb. Our data indicate that, in SGs, a minority of B cell clusters represent genuine GC cells, while the majority manifest features of being type 2 transitional B cells and marginal zone cells. Interestingly, both types of B cell aggregates include autoreactive B cells.

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“…Furthermore, MCL carrying a high mutational load may originate from cells strongly influenced by the germinal center microenvironment. Finally, the progenitor cells of cases with a low number of somatic mutations may derive from cells of the marginal zone, intermediate cells between naive and germinal center cells already expressing AID or transitional B cells resembling murine B-1 B cells (11,12).…”

Section: Cell(s) Of Origin and Ontogenymentioning

confidence: 99%

Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

302

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Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients. IntroductionMantle cell lymphoma (MCL) is a B cell malignancy with a broad spectrum of clinical, pathological, and biological features. The identification of the translocation event t(11;14)(q13;q32) and the resulting cyclin D1 overexpression were of paramount importance in recognizing the clinical and biological diversity of this tumor. In addition to this constitutive dysregulation of the cell cycle, other mechanisms such as DNA damage response alterations and activation of cell survival pathways are integrated to drive MCL pathogenesis (1, 2). New observations are expanding our views on the ontogeny and pathogenesis of this lymphoma. Furthermore, these new insights into MCL oncogenesis are promoting the development of new therapeutic strategies, intended to target the molecular mechanism of the disease, and opening up new clinical perspectives for optimal diagnosis and management of the patients.

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

Cited by 51 publications

References 38 publications

AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations

AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations

Ectopic Germinal Centers Are Rare in Sjögren’s Syndrome Salivary Glands and Do Not Exclude Autoreactive B Cells

Molecular pathogenesis of mantle cell lymphoma

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