Universal N-glycosylation sites introduced into the B-cell receptor of follicular lymphoma by somatic mutation: a second tumorigenic event?

McCann, Katy J.; Johnson, Peter; Stevenson, Freda K.; Ottensmeier, Christian

doi:10.1038/sj.leu.2404095

Cited by 31 publications

(27 citation statements)

References 10 publications

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“…11 Additionally, in the present large series of HCL, we observed an irrelevant incidence of novel N-glycosylation sites introduced by somatic mutation in the tumor IgV region (<6%), similar to that observed in normal memory B cells or in transformed memory and marginal zone B cells (Online Supplementary Tables S1 and S2). 5,6,19,53 Since N-glycosylation sites are specifically introduced in the IgV region of germinal center-derived lymphomas, while they are rare in marginal zone or post-germinal center B-cell neoplasms, 5,6,19,53 our results provide further support to the hypothesis that HCL originates from non-germinal center derived B cells.…”

Section: Discussionsupporting

confidence: 76%

“…4 Selective stimuli to the tumor BCR may be of different types, including viral or bacterial antigens, or, in germinal center-derived lymphomas, stromal elements acting on N-glycosylated residues acquired by somatic mutation. 5,6 Analysis of the selective influences on the tumor BCR has often been hampered in HCL by the rarity of the disease, and only small series of cases have been analyzed to date. 1 In small series of HCL, we and others have observed that most HCL carry mutated IGH variable region (V) genes, with low levels of intraclonal heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

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Selective influences in the expressed immunoglobulin heavy and light chain gene repertoire in hairy cell leukemia

Forconi¹,

Sozzi²,

Rossi³

et al. 2008

Haematologica

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Selective influences in the expressed immunoglobulin heavy and light chain gene repertoire in hairy cell leukemia

Forconi¹,

Sozzi²,

Rossi³

et al. 2008

Haematologica

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“…In contrast to MALT-eMZL, follicular lymphoma cells appear to acquire a pathogenetic role for the B-cell receptor through creation of novel unusual glycosylation sites within CDR regions by ongoing somatic hypermutation. 9 This process would be expected to be T-cell-independent and would be consistent with an unperturbed T-helper cell repertoire as observed in this study.…”

mentioning

confidence: 71%

The peripheral helper T-cell repertoire in untreated indolent B-cell lymphomas: evidence for antigen-driven lymphomagenesis

et al. 2008

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“…This model is consistent with the detection of common BCR mutations in FL. 18,19 Such mutations might promote close associations of BCR subunits, alter the interaction of BCR subunits with coreceptors on the surface of the tumor B cells, or enable additional tumor-stromal interactions. Differences in the expression of the BCR or coreceptors that positively (CD19) and negatively (CD22) regulate BCR signaling might also account for altered signaling that we observed in FL B cells (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

“…Supporting the idea that BCR signaling might be altered in FL, evidence exists that the BCR in these malignant cells has somatic mutations that enable N-glycosylation. 18,19 If BCR signaling supports the survival of lymphoma B cells, we would expect to see amplified signaling specific to FL B cells. However, BCR signaling might also induce apoptosis or cell cycle arrest in lymphoma B cells.…”

Section: Introductionmentioning

confidence: 99%

Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells

Irish

Czerwinski

Nolan

et al. 2006

Blood

128

116

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IntroductionB-cell receptor (BCR) signaling regulates several B-cell fate decisions throughout development, [1][2][3][4][5] and continued expression of the signaling subunits of the BCR is required for survival of mature B cells. 6,7 Because BCR signaling is so closely linked with survival and proliferation of B cells, it is thought that alterations in BCR signaling may support lymphomagenesis. 8,9 We have previously developed an approach to identify profiles of aberrant signaling in individual malignant or normal cells. 10,11 The identification of altered BCR signaling in lymphoma cells might provide new opportunities to improve cancer therapy, as targeted inhibition of signaling associated with cancer progression and maintenance has proved successful for other malignancies. 12 This study of BCR signaling in lymphoma builds on extensive prior work mapping the BCR signaling events 13 and our own studies of BCR signaling kinetics in primary peripheral blood B cells. 14 Here we measure BCR-mediated Btk, Syk, Erk1/2, and p38 ( Figure 1A) signaling kinetics within different types of B cells in follicular lymphoma (FL) tumor specimens. These 4 signaling nodes are highlighted in a model of BCR signaling activation and regulation. Btk and Syk are key proximal signal transducers required for effective BCR-mediated activation of PI3K and PLC␥2. [15][16][17] As such, changes to BCR signaling in lymphoma might be expected to alter the activity of Btk and Syk. Downstream effectors of BCR signaling include the MAPK family proteins Erk1/2 and p38.Signaling originating at the BCR can either promote proliferation or initiate programmed cell death, and it is not yet known whether BCR signaling in FL B cells is unaltered, amplified, or suppressed. Supporting the idea that BCR signaling might be altered in FL, evidence exists that the BCR in these malignant cells has somatic mutations that enable N-glycosylation. 18,19 If BCR signaling supports the survival of lymphoma B cells, we would expect to see amplified signaling specific to FL B cells. However, BCR signaling might also induce apoptosis or cell cycle arrest in lymphoma B cells. The effectiveness of monoclonal antibody therapy directed against the idiotype of the lymphoma BCR 20,21 has been directly correlated with the ability of these antibodies to induce BCR signal transduction. 22 Thus, there is a need to determine whether BCR signal transduction is altered in lymphoma, to identify the direction of this alteration (potentiation or attenuation), and to dissect whether signaling changes are specific to lymphoma B cells or common to all B cells at the tumor site. The latter might occur if the lymphoma tumor microenvironment supported altered BCR signaling, in which case both normal and malignant B cells would be expected to show abnormal signaling.Flow cytometry is particularly well suited to address these needs as it can measure multiple signaling events in individual cells while simultaneously distinguishing among cell subsets. 10 Measuring several phosphoproteins by flow ...

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Universal N-glycosylation sites introduced into the B-cell receptor of follicular lymphoma by somatic mutation: a second tumorigenic event?

Cited by 31 publications

References 10 publications

Selective influences in the expressed immunoglobulin heavy and light chain gene repertoire in hairy cell leukemia

Selective influences in the expressed immunoglobulin heavy and light chain gene repertoire in hairy cell leukemia

The peripheral helper T-cell repertoire in untreated indolent B-cell lymphomas: evidence for antigen-driven lymphomagenesis

Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells

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