Mutations of multiple genes cause deregulation of NF-B in diffuse large B-cell lymphoma

Mara Compagno, Wei Keat Lim, Adina Grunn, Subhadra V. Nandula, Manisha Brahmachary, Qiong Shen, Francesco Bertoni, Maurilio Ponzoni, Marta Scandurra, Andrea Califano, Govind Bhagat, Amy Chadburn, Riccardo Dalla-Favera, Laura Pasqualucci

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Abstract

Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-B transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-B activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that>50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-B. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-B responses, is most commonly affected, with 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-B. Thus, our results demonstrate that NF-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-B responses.

Original languageEnglish
Pages (from-to)717-721
Number of pages5
JournalNature
Volume459
Issue number7247
DOIs
Publication statusPublished - Jun 4 2009

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Lymphoma, Large B-Cell, Diffuse
B-Lymphocytes
Mutation
TNF Receptor-Associated Factor 2
Genes
Germinal Center
TNF Receptor-Associated Factor 5
Neoplasms
Sequence Deletion
Gene Silencing
Missense Mutation
B-Cell Chronic Lymphocytic Leukemia
Ubiquitin
Transcriptome
Lymphoma
Apoptosis
Cell Line
Enzymes
Growth

ASJC Scopus subject areas

  • General

Cite this

Compagno, M., Lim, W. K., Grunn, A., Nandula, S. V., Brahmachary, M., Shen, Q., ... Pasqualucci, L. (2009). Mutations of multiple genes cause deregulation of NF-B in diffuse large B-cell lymphoma. Nature, 459(7247), 717-721. https://doi.org/10.1038/nature07968

Mutations of multiple genes cause deregulation of NF-B in diffuse large B-cell lymphoma. / Compagno, Mara; Lim, Wei Keat; Grunn, Adina; Nandula, Subhadra V.; Brahmachary, Manisha; Shen, Qiong; Bertoni, Francesco; Ponzoni, Maurilio; Scandurra, Marta; Califano, Andrea; Bhagat, Govind; Chadburn, Amy; Dalla-Favera, Riccardo; Pasqualucci, Laura.

In: Nature, Vol. 459, No. 7247, 04.06.2009, p. 717-721.

Research output: Contribution to journalArticle

Compagno, M, Lim, WK, Grunn, A, Nandula, SV, Brahmachary, M, Shen, Q, Bertoni, F, Ponzoni, M, Scandurra, M, Califano, A, Bhagat, G, Chadburn, A, Dalla-Favera, R & Pasqualucci, L 2009, 'Mutations of multiple genes cause deregulation of NF-B in diffuse large B-cell lymphoma', Nature, vol. 459, no. 7247, pp. 717-721. https://doi.org/10.1038/nature07968
Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q et al. Mutations of multiple genes cause deregulation of NF-B in diffuse large B-cell lymphoma. Nature. 2009 Jun 4;459(7247):717-721. https://doi.org/10.1038/nature07968
Compagno, Mara ; Lim, Wei Keat ; Grunn, Adina ; Nandula, Subhadra V. ; Brahmachary, Manisha ; Shen, Qiong ; Bertoni, Francesco ; Ponzoni, Maurilio ; Scandurra, Marta ; Califano, Andrea ; Bhagat, Govind ; Chadburn, Amy ; Dalla-Favera, Riccardo ; Pasqualucci, Laura. / Mutations of multiple genes cause deregulation of NF-B in diffuse large B-cell lymphoma. In: Nature. 2009 ; Vol. 459, No. 7247. pp. 717-721.
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abstract = "Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-B transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-B activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that>50{\%} of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-B. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-B responses, is most commonly affected, with 30{\%} of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-B. Thus, our results demonstrate that NF-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-B responses.",
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AU - Califano, Andrea

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N2 - Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-B transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-B activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that>50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-B. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-B responses, is most commonly affected, with 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-B. Thus, our results demonstrate that NF-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-B responses.

AB - Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-B transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-B activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that>50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-B. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-B responses, is most commonly affected, with 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-B. Thus, our results demonstrate that NF-B activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-B responses.

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