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G-Rich Proto-Oncogenes Are Targeted for Genomic Instability in B-Cell Lymphomas

Departments of ¹ Immunology and ² Biochemistry, University of Washington School of Medicine, Seattle, Washington

Requests for reprints: Nancy Maizels, Department of Immunology, University of Washington School of Medicine, 1959 Northeast Pacific Street, Box 357650, Seattle, WA 98195. Phone 206-221-6876; Fax: 206-221-6781; E-mail: maizels{at}u.washington.edu.

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. [Cancer Res 2007;67(6):2586–94]

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