G-rich proto-oncogenes are targeted for genomic instability in B-cell lymphomas.
Diffuse large B-cell lymphoma is the most common lymphoid malignancy in adults. It is a heterogeneous disease with variability in outcome. Genomic instability of a subset of proto-oncogenes, including c-MYC, BCL6, RhoH, PIM1, and PAX5, can contribute to initial tumor development and has been correlated with poor prognosis and aggressive tumor growth. Lymphomas in which these proto-oncogenes are unstable derive from germinal center B cells that express activation-induced deaminase (AID), the B-cell-specific factor that deaminates DNA to initiate immunoglobulin gene diversification. Proto-oncogene instability is evident as both aberrant hypermutation and translocation, paralleling programmed instability which diversifies the immunoglobulin loci. We have asked if genomic sequence correlates with instability in AID-positive B-cell lymphomas. We show that instability does not correlate with enrichment of the WRC sequence motif that is the consensus for deamination by AID. Instability does correlate with G-richness, evident as multiple runs of the base guanine on the nontemplate DNA strand. Extending previous analysis of c-MYC, we show experimentally that transcription of BCL6 and RhoH induces formation of structures, G-loops, which contain single-stranded regions targeted by AID. We further show that G-richness does not characterize translocation breakpoints in AID-negative B- and T-cell malignancies. These results identify G-richness as one feature of genomic structure that can contribute to genomic instability in AID-positive B-cell malignancies.
Duquette
Michelle L
ML
Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Huber
Michael D
MD
Maizels
Nancy
N
D001402:B-Lymphocytes / Q000201:enzymology / Q000473:pathology; D042822:Genomic Instability; D006151:Guanosine / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000235:genetics*; D009690:Nucleic Acid Conformation; D009700:Nucleoside Deaminases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes; D014158:Transcription, Genetic
D007136:Immunoglobulins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D006151:Guanosine; D009700:Nucleoside Deaminases