Ongoing immunoglobulin gene mutations in mantle cell lymphomas

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Mantle cell lymphomas (MCL) often exhibit a follicular growth pattern, suggesting tumor cells colonize B-cell follicles.
• The germinal center environment, crucial for B-cell maturation, might influence MCL expansion through antigen stimulation.

Purpose of the Study:

• To investigate the role of antigen stimulation in MCL development by examining ongoing immunoglobulin (Ig) mutations.
• To determine the origin of MCL by analyzing Ig gene sequences and mutation status.

Main Methods:

• Analysis of ongoing Ig mutations in tumor cells from five MCL cases, including lymphomatous polyposis (LP).
• Microdissection of tumor cells from colonized follicles in two MCL cases.
• Sequencing of rearranged Ig genes to assess homology to germline sequences and identify somatic mutations.

Main Results:

• Consensus Ig V gene sequences in four MCLs showed high homology to published germlines, often associated with autoantibodies.
• One MCL case exhibited a consensus Ig VH sequence with 95.5% homology to the closest germline, possibly indicating an unknown germline or rare somatic mutations.
• Ongoing mutations within the tumor clone were detected in two cases: one LP with multiple lesions and one nodal MCL with colonized follicles.

Conclusions:

• MCLs likely originate from pre-germinal center B cells, potentially autoreactive clones.
• The presence of ongoing mutations suggests antigen stimulation may contribute to clonal expansion in a subset of MCL patients.