Medizinische Universität Graz - Research portal
Selected Publication:
Pasqualucci, L; Neumeister, P; Goossens, T; Nanjangud, G; Chaganti, RS; Küppers, R; Dalla-Favera, R.
Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas.
Nature. 2001; 412(6844):341-346
Doi: 10.1038/35085588
Web of Science
PubMed
FullText
FullText_MUG
- Co-authors Med Uni Graz
- Neumeister Peter
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- 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 represent the major contributor to lymphomagenesis.
- Find related publications in this database (using NLM MeSH Indexing)
- B-Cell-Specific Activator Protein -
- B-Lymphocytes -
- DNA Mutational Analysis -
- DNA-Binding Proteins -
- Genes, myc -
- Germinal Center - cytology
- Humans - cytology
- Lymphoma, B-Cell - genetics
- Lymphoma, Large-Cell, Diffuse - genetics
- Molecular Sequence Data - genetics
- Mutation - genetics
- Proteins - genetics
- Proto-Oncogenes - genetics
- Transcription Factors - genetics