Target Sequence Accessibility Limits Activation-Induced Cytidine Deaminase Activity in Primary Mediastinal B-Cell Lymphoma

Popov, Sergey W.; Moldenhauer, Gerhard; Wotschke, Beate; Brüderlein, Silke; Barth, Thomas F.E.; Dorsch, Karola; Ritz, Olga; Möller, Peter; Leithäuser, Frank

doi:10.1158/0008-5472.can-06-2166

Cited by 8 publications

(6 citation statements)

References 50 publications

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“…37 Interestingly, activationinduced cytidine deaminase (AID), a gene that plays a key role in SHM and class switch recombination, has been shown to be constitutively expressed in PMBCL and the PMBCL-derived cell line KARPAS1106P 38 showed ongoing SHM, but not class switch recombination, involving IG genes and BCL6. 39 Although, taken together, these data are consistent with a germinal center origin of PMBCL and migration into the thymus, another potential explanation is that PMBCL is derived from AID-expressing non-germinal center B lymphocytes residing in the medullary thymus. 40 …”

Section: Pathology and Clinical Featuressupporting

confidence: 55%

The molecular pathogenesis of primary mediastinal large B-cell lymphoma

Steidl

Gascoyne

2011

Blood

186

148

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Primary mediastinal large B-cell lymphoma (PMBCL) is a recognized nonHodgkin lymphoma entity with unique pathologic, clinical, and molecular characteristics distinct from those of other diffuse large B-cell lymphomas. Immunohistochemical characterization and molecular studies strongly suggest that PMBCL is of germinal center or postgerminal center origin. Pivotal gene expression profiling work defined major deregulated pathway activities that overlap with Hodgkin lymphoma and prompted a more detailed analysis of candidate genes. In particular, the nuclear factor-B and the Janus Kinase-Signal Transducer and Activator of Transcription signaling pathways are targeted by multiple genomic hits, and constitutive activity of both pathways can be considered molecular hallmark alterations of PMBCL. Moreover, data are emerging giving unique insight into remodeling of the epigenome that affects transcriptional regulation of a multitude of genes. More recently, the tumor microenvironment of PMBCL has shifted into focus based on a number of gene perturbations altering expression of surface molecules that contribute to immune escape. These findings highlight the importance of immune privilege in the pathogenesis of PMBCL and suggest that disrupting crosstalk between the tumor cells and the microenvironment might be a rational new therapeutic target in conjunction with traditional treatment strategies.

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Section: Pathology and Clinical Featuressupporting

confidence: 55%

The molecular pathogenesis of primary mediastinal large B-cell lymphoma

Steidl

Gascoyne

2011

Blood

186

148

View full text Add to dashboard Cite

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“…1b,c). We observed several genomic 'hotspot' regions with high mutation frequency in PM-7, including the BCL6 oncogene 21,22 and the λ light-chain locus, known targets of somatic hypermutation. Somatic variant calling, including of SNVs and indels, identified 20,044 intronic (9,425 and 10,619), 32,565 intergenic (16,176 and 16,389), 22 5′ UTR (11 and 11), 81 3′ UTR (39 and 42) and 299 coding-region (148 and 151) mutations in the PM-2 and PM-7 genomes, respectively.…”

Section: Somatic Mutations Discovered By Next-generation Sequencingmentioning

confidence: 96%

Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma

et al. 2014

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Classical Hodgkin lymphoma and primary mediastinal B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by whole-genome and whole-transcriptome sequencing recurrent somatic coding-sequence mutations in the PTPN1 gene. Mutations were found in 6 of 30 (20%) Hodgkin lymphoma cases, in 6 of 9 (67%) Hodgkin lymphoma-derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in Hodgkin lymphoma cell line KM-H2 resulted in hyperphosphorylation and overexpression of downstream oncogenic targets. Our data establish PTPN1 mutations as new drivers in lymphomagenesis.

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“…50 Interestingly, PMBL constitutively expresses AID although neoplastic cells are IGnegative, shows a low frequency of CSR and lack of ongoing SHM. 51 Whether the large-scale CN-LOH events identified in PMBL could be attributed to the enhanced activity of the AID/APOBEC pathway or other repair pathways operating in B-cell, like the ubiquitous Base Excision Repair (BER) pathway, 52 needs further investigations. Specific association of large-scale CN-LOH and PMBL might suggest a key role of the mediastinal environment in the induction of these genetic events.…”

Section: Discussionmentioning

confidence: 99%

Primary mediastinal large B‐cell lymphoma is characterized by large‐scale copy‐neutral loss of heterozygosity

Tuveri

Debackere

Marcelis

et al. 2022

Genes Chromosomes & Cancer

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Development of primary mediastinal B‐cell lymphoma (PMBL) is driven by cumulative genomic aberrations. We discovered a unique copy‐neutral loss of heterozygosity (CN‐LOH) landscape of PMBL which distinguishes this tumor from other B‐cell malignancies, including the biologically related diffuse large B‐cell lymphoma. Using single nucleotide polymorphism array analysis we identified large‐scale CN‐LOH lesions in 91% (30/33) of diagnostic PMBLs and both investigated PMBL‐derived cell lines. Altogether, the cohort showed 157 extra‐large (25.3–248.4 Mb) CN‐LOH lesions affecting up to 14 chromosomes per case (mean of 4.4) and resulting in a reduction of heterozygosity an average of 9.9% (range 1.3–51%) of the genome. Predominant involvement of terminal chromosomal segments suggests the implication of B‐cell specific crossover events in the pathogenesis of PMBL. Notably, CN‐LOH stretches non‐randomly clustered on 6p (60%), 15 (37.2%), and 17q (40%), and frequently co‐occurred with homozygous mutations in the MHC I (6p21), B2M (15q15), and GNA13 (17q23) genes, respectively, as shown by preliminary whole‐exome/genome sequencing data. Altogether, our findings implicate CN‐LOH as a novel and distinct mutational process contributing to the molecular pathogenesis of PMBL. The aberration acting as “second hit” in the Knudson hypothesis, ranks as the major mechanism converting to homozygosity the PMBL‐related driver genes. Screening of the cohort of 199 B cell leukemia/lymphoma whole‐genomes revealed significant differences in the CN‐LOH landscape of PMBL and other B‐cell malignancies, including the biologically related diffuse large B‐cell lymphoma.

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Target Sequence Accessibility Limits Activation-Induced Cytidine Deaminase Activity in Primary Mediastinal B-Cell Lymphoma

Cited by 8 publications

References 50 publications

The molecular pathogenesis of primary mediastinal large B-cell lymphoma

The molecular pathogenesis of primary mediastinal large B-cell lymphoma

Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma

Primary mediastinal large B‐cell lymphoma is characterized by large‐scale copy‐neutral loss of heterozygosity

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