Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma

Gaïdano, Gianluca; Pasqualucci, Laura; Capello, Daniela; Berra, Eva; Deambrogi, Clara; Rossi, Davide; Larocca, Luigi Maria; Gloghini, Annunziata; Carbone, Antonino; Dalla‐Favera, Riccardo

doi:10.1182/blood-2002-11-3606

Cited by 130 publications

(113 citation statements)

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“…Eight cases of CLL (cases [1][2][3][4][5][6][7][8] showed no transformation during the clinical course of the disease, 13 cases (cases 9-21) developed RT and eight cases (cases [22][23][24][25][26][27][28][29] showed PLT. In seven cases of RT (cases 9-15), both CLL and DLBL samples were available for analysis.…”

Section: Pathological Samplesmentioning

confidence: 99%

“…[5][6][7][8][9] Aberrant somatic hypermutation is considered as a malfunction of somatic hypermutation (SHM), which is a physiological process in the immunoglobulin (Ig) variable genes of germinal center (GC) B-cells promoting affinity maturation. 10 Aberrant somatic hypermutation induces genomewide genetic instability by affecting multiple loci outside the Ig genes, including c-MYC, RhoH, Pax-5 and Pim-1 protooncogenes.…”

Section: Introductionmentioning

confidence: 99%

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Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation

et al. 2006

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Chronic lymphocytic leukemia (CLL) is an indolent B-cell nonHodgkin's lymphoma that may transform into higher-grade lymphoma. The transformation involves an increased number of prolymphocytic cells, termed prolymphocytic transformation (PLT) or the development of diffuse large B-cell lymphoma (DLBL), also referred to as Richter's transformation (RT). To analyze whether activation-induced cytidine deaminase (AID), which is essential for somatic hypermutation (SHM) of normal B-cells, and malfunction of SHM termed aberrant somatic hypermutation (ASHM) are associated with higher-grade transformation of CLL, AID mRNA expression and the mutation pattern of c-MYC, PAX-5 and RhoH genes were analyzed in eight cases of CLL without transformation and in 21 cases that showed RT or PLT. Chronic lymphocytic leukemia cases, which showed no transformation or eventually transformed into higher-grade lymphoma, showed low levels of AID mRNA expression and low frequency of mutations of c-MYC, PAX-5 and RhoH genes. In both RT and PLT, high-levels of AID mRNA expression and high-frequency mutations of c-MYC, PAX-5 and RhoH genes were detected. These results indicate that AID expression and ASHM are associated with higher-grade transformation of CLL and provide further evidences that AID expression and ASHM may be activated during the clonal history of B-cell lymphomas.

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Section: Pathological Samplesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation

et al. 2006

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“…The mutation frequency for nucleotides occurring in the context of an RGYW/WRCY motif was compared to the expected mutation frequency by the goodness-of-fit w 2 -test. 23 …”

Section: Molecular Analysis Of Bcl-6 Mutationsmentioning

confidence: 99%

A spindle cell variant of diffuse large B-cell lymphoma possesses genotypic and phenotypic markers characteristic of a germinal center B-cell origin

et al. 2006

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Lymphoma with prominent spindle cell features, the so-called spindle cell lymphoma, is an unusual morphological variant of diffuse large B-cell lymphoma. Five new cases of spindle cell lymphoma have been analyzed by a multiparameter approach in order to clarify its clinical and biological features. All patients presented advanced stage disease with extranodal involvement. Vagina was the most common extranodal site. All patients received chemotherapy and are alive in complete remission. Morphologically, all five cases exhibited proliferation of spindle cells with a vaguely storiform pattern highly suggestive of spindle cell neoplasms of nonlymphoid origin. In contrast, the results of immunohistochemical analysis indicated that all five cases were hematolymphoid neoplasms of the B-cell lineage. These lymphomas consisted of a B-cell clonal population which exhibited somatic immunoglobulin and BCL-6 mutations as well as BCL-6 protein expression. The neoplastic spindle cells therefore closely resemble B cells residing in the germinal center. The absence of MUM1 expression in neoplastic spindle cells suggested that neoplastic spindle cells may be related to the early phases of intragerminal center maturation of B cells. The germinal center phenotype, with restricted expression of BCL-6, was associated with the presence of a primary extranodal origin, normal lactate dehydrogenase levels, and good response to treatment.

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“…General models of chronic antigen stimulation, immunosuppression, cytokine dysregulation, and genetic changes have been proposed; some genetic alterations including rearrangements of BCL6, a zinc-finger transcriptional repressor and aberrant somatic hypermutation, have been reported in both AIDS and non-AIDS diffuse large B-cell lymphomas. [28][29][30][31] Epstein-Barr viral infection has been reported in 30 and 80-90% of the centroblastic and immunoblastic variants of AIDS-related diffuse large B-cell lymphomas, respectively. 22,31 In contrast to diffuse large B-cell lymphoma in immunocompetent patients, there are only a limited number of gene expression profiling studies of AIDS-related diffuse large B-cell lymphoma.…”

Section: Aids and Non-aids Diffuse Large B-cell Lymphoma R Madan Et Almentioning

confidence: 99%

AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles

et al. 2006

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Based on gene expression profiling, diffuse large B-cell lymphomas arising in immunocompetent patients can be divided into germinal center and activated B-cell types. Since little is known about acquired immunodeficiency syndrome associated diffuse large B-cell lymphomas, we tested whether the protein expression of germinal center and activated B-cell markers differed between acquired immunodeficiency syndrome (AIDS) vs non-AIDS diffuse large B-cell lymphomas. We immunohistochemically stained tissue microarrays of 39 de novo diffuse large B-cell lymphomas: 12 AIDS associated and 27 non-AIDS, with germinal center (BCL6, CD10, CyclinH) and activated B-cell markers (MUM1, CD138, PAK1, CD44, BCL2). We scored each case for percent positive cells (0-19% ¼ 0; 20-49% ¼ 1; 50-100% ¼ 2). The activated B-cell and germinal center summation scores of each case were used as (x, y) coordinate data points to construct two-dimensional contour-frequency plots. The contour plot of non-AIDS diffuse large B-cell lymphomas showed two distinct clusters: a cluster with a high germinal center phenotype (cluster 1) and a cluster with a high activated B-cell phenotype (cluster 3). In contrast, the AIDS-related diffuse large B-cell lymphomas formed a single aggregate (cluster 2) (P ¼ 0.02, Fisher exact test). When the contour plots of the AIDS-related and the non-AIDS cases were superimposed, cluster 2 of the AIDS cases expressed an intermediate germinal center/activated B-cell phenotype compared to clusters 1 and 3 of the non-AIDS diffuse large B-cell lymphomas. Our results confirm that non-AIDS diffuse large B-cell lymphomas segregate into two groups with either germinal center or activated B-cell phenotype. We report the new finding that the AIDS status of the patient predicts the immunophenotype of the diffuse large B-cell lymphomas. We also describe a novel method for displaying immunohistochemical expression data using twodimensional contour-frequency plots. Materials and methods Lymphoma SamplesWe performed a retrospective study of 56 diffuse large B-cell lymphomas (23 AIDS-related and 33 non-AIDS) that were retrieved from the archives of

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Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma

Abstract: The pathogenesis of AIDS-related nonHodgkin lymphomas (AIDS-NHLs

Cited by 130 publications

References 44 publications

Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation

Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation

A spindle cell variant of diffuse large B-cell lymphoma possesses genotypic and phenotypic markers characteristic of a germinal center B-cell origin

AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles

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