Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas
Abstract
Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells. Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1, MYC, RhoH/TTF (ARHH) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may repre…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Most described cases show that RHOH is a hypermutable gene locus targeted by aberrant somatic hypermutation.
“Although there are reports where structural changes in the 4p13 region could be linked to translocation of the RHOH gene [32-34], most of the cases described so far show that RHOH is a hypermutable gene locus and targeted by aberrant somatic hypermutation [35].”
From The small GTPase RhoH is an atypical regulator of haematopoietic cells (2008) · cites this paper as [35]
In DLBCL, around 50% of cases harbour aberrant mutations for PIM1, PAX5, MYC and RHOH.
“In DLBCL, around 50% of the cases were found to harbour aberrant mutations for PIM1, PAX5, MYC and RHOH, respectively [35].”
From The small GTPase RhoH is an atypical regulator of haematopoietic cells (2008) · cites this paper as [35]
Cites
Genetic instabilities in human cancers
Lengauer, C., Kinzler, K. W., & Vogelstein, B. (1998) · Nature · doi:10.1038/25292 · Cited by 4,168 · cited 1× · see citing works
“gif" NDATA ITEM> ]> Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repai”
Flagged first, then by citations
Cited by
Sorted by citations
Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy
Lohr, J. G., Stojanov, P., Carter, S. L., Cruz-Gordillo, P., Lawrence, M. S., Auclair, D., Sougnez, C., Knoechel, B., Gould, J., Saksena, G., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2013.12.015 · Cited by 988 · see citing works
Multiple myeloma: evolving genetic events and host interactions
Kuehl, W. M., & Bergsagel, P. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc746 · Cited by 818 · see citing works
Signatures of mutation and selection in the cancer genome
Bignell, G. R., Greenman, C. D., Davies, H., Butler, A. P., Edkins, S., Andrews, J. M., Buck, G., Chen, L., Beare, D., Latimer, C., et al. (2010) · Nature · doi:10.1038/nature08768 · Cited by 707 · see citing works
Error-Prone Repair DNA Polymerases in Prokaryotes and Eukaryotes
Goodman, M. F. (2002) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.71.083101.124707 · Cited by 727 · see citing works
Ranuncolo, S. M., Polo, J. M., Dierov, J., Singer, M., Kuo, T., Greally, J., Green, R., Carroll, M., & Melnick, A. (2007) · Nature Immunology · doi:10.1038/ni1478 · Cited by 278 · see citing works
Mottok, A., Renné, C., Seifert, M., Oppermann, E., Bechstein, W., Hansmann, M.-L., Küppers, R., & Bräuninger, A. (2009) · Blood · doi:10.1182/blood-2009-06-225839 · Cited by 124 · see citing works
Self-citationRelated Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination
Hwang*, J. K., Alt*, F. W., & Yeap, L.-S. (2015) · Microbiology Spectrum · doi:10.1128/microbiolspec.mdna3-0037-2014 · Cited by 126 · see citing works
BCL6 represses CHEK1 and suppresses DNA damage pathways in normal and malignant B-cells
Ranuncolo, S. M., Polo, J. M., & Melnick, A. (2008) · Blood Cells, Molecules, and Diseases · doi:10.1016/j.bcmd.2008.02.003 · Cited by 116 · see citing works
EPELDEGUI, M., HUNG, Y., MCQUAY, A., AMBINDER, R., & MARTINEZMAZA, O. (2007) · Molecular Immunology · doi:10.1016/j.molimm.2006.03.018 · Cited by 93 · see citing works
Choi, J., Lee, K., Ingvarsdottir, K., Bonasio, R., Saraf, A., Florens, L., Washburn, M. P., Tadros, S., Green, M. R., & Busino, L. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0084-5 · Cited by 50 · see citing works
The small GTPase RhoH is an atypical regulator of haematopoietic cells
Fueller, F., & Kubatzky, K. F. (2008) · Cell Communication and Signaling · doi:10.1186/1478-811x-6-6 · Cited by 40 · see citing works
RhoH GTPase: A Key Regulator of Hematopoietic Cell Proliferation and Apoptosis?
Gu, Y., Zheng, Y., & Williams, D. A. (2005) · Cell Cycle · doi:10.4161/cc.4.2.1395 · Cited by 20 · see citing works
- Authors
- Pasqualucci, L., Neumeister, P., Goossens, T., Nanjangud, G., Chaganti, R. S. K., Küppers, R., & Dalla-Favera, R.
- Affiliations
- Columbia University (US)
- University of Cologne (DE)
- Memorial Sloan Kettering Cancer Center (US)
- Venue
- Nature
- Published
- 2001-07
- Volume
- 412
- Issue
- 6844
- Pages
- 341-346
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1506411711
- Cited by
- 1,032
- References
- 1
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 27 · 2023: 34 · 2022: 28 · 2021: 28 · 2020: 24 · 2019: 37 · 2018: 32 · 2017: 30 · 2016: 32 · 2015: 57 · 2014: 48 · 2013: 41 · 2012: 65
- FWCI
- 25.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Keywords
- somatic hypermutation, diffuse large cell lymphoma, B-cell lymphoma, proto-oncogenes, c-Myc, PIM-1, PAX5, chromosomal translocation, lymphomagenesis, germinal center, genomic instability, DNA double-strand breaks, immunoglobulin variable region
- MeSH terms
- B-Lymphocytes, DNA Mutational Analysis, DNA-Binding Proteins, Humans, Molecular Sequence Data, Mutation, Proteins, Proto-Oncogenes, Transcription Factors, Genes, myc, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Germinal Center, PAX5 Transcription Factor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
