期刊
INTERNATIONAL IMMUNOLOGY
卷 22, 期 11, 页码 875-887出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxq441
关键词
germinal center; Ig genes; lineage trees; lymphomas; somatic hypermutation
类别
资金
- Israel Science Foundation [759/01, 546/05, 270/09]
- Israel Cancer Research Fund
- Human Frontiers Science Program [RGY0025/2003-C]
- Swedish Foundation for Strategic Research
- Cancer Research UK [7576]
- Yeshaya Horowitz Association through a Center for Complexity Science
- Ministry of Science and Technology
- Bar-Ilan University
- Mina and Everard Goodman Faculty of Life Sciences
Follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL) and primary central nervous system lymphoma are B cell malignancies. FL and DLBCL have a germinal center origin. We have applied mutational analyses and a novel algorithm for quantifying shape properties of mutational lineage trees to investigate the nature of the diversification, somatic hypermutation and selection processes that affect B cell clones in these malignancies and reveal whether they differ from normal responses. Lineage tree analysis demonstrated higher diversification and mutations per cell in the lymphoma clones. This was caused solely by the longer diversification times of the malignant clones, as their recent diversification processes were similar to those of normal responses, implying similar mutation frequencies. Since previous analyses of antigen-driven selection were shown to yield false positives, we performed a corrected analysis of replacement and silent mutation patterns, which revealed selection against replacement mutations in the framework regions, responsible for the structural integrity of the B cell receptor, but not for positive selection for replacements in the complementary determining regions. Most replacements, however, were neutral or conservative, suggesting that if at all selection operates in these malignancies it is for structural B cell receptor integrity but not for antigen binding.
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