Somatic hypermutation in normal and transformed human B cells

Area of Science:

• Immunology and Cancer Biology
• Hematology

Background:

• Peripheral blood B cells (IgM+IgD+ and CD5+) are typically pre-germinal center (GC) with unmutated V genes.
• Memory B cells, generated in the GC, have somatically mutated V-region genes and include class-switched, IgM-only, and CD27+IgM+IgD+ subsets.

Purpose of the Study:

• To identify the developmental stage of progenitor cells in human B-cell lymphomas.
• To compare rearranged V-region genes of lymphomas with normal B-cell subsets to determine tumor origins.

Main Methods:

• Analysis of rearranged V-region genes from human B-cell lymphomas.
• Comparison with V-region genes from normal human B-cell subsets.
• Sequence analysis of rearranged V genes from single tonsillar germinal center B cells.

Main Results:

• Most B-cell non-Hodgkin lymphomas and Hodgkin/Reed-Sternberg (HRS) cells originate from GC or post-GC B cells.
• Tumor precursors are selected for functional antigen receptors, except for HRS cells in classical Hodgkin's disease, which appear 'crippled'.
• Somatic hypermutation introduces deletions/insertions into V-region genes more frequently than previously thought.

Conclusions:

• B-cell lymphomas and Hodgkin's disease arise from germinal center-derived B cells.
• The frequent introduction of deletions/insertions during somatic hypermutation may explain heavy chain disease and oncogene translocations in lymphomas.