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Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches
Published on: April 20, 2021
Evidence of canonical somatic hypermutation in hairy cell leukemia
Evgeny Arons1, Laura Roth, Jeffrey Sapolsky
1Laboratories of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Insights
Hairy cell leukemia (HCL) subtypes show distinct B-cell receptor mutation patterns. Classic HCL resembles chronic lymphocytic leukemia (CLL) and normal B cells, suggesting antigen recognition, while variant HCL may arise differently.
Area of Science:
- Immunology
- Hematology
- Oncology
Background:
- Hairy cell leukemia (HCL) is a rare B-cell malignancy with classic (HCLc) and variant (HCLv) forms.
- Understanding B-cell receptor (BCR) genetics, including somatic hypermutation (SHM), aids in differentiating HCL subtypes and normal B cells.
Purpose of the Study:
- To compare the SHM features of B-cell receptors in classic HCL (HCLc), variant HCL (HCLv), chronic lymphocytic leukemia (CLL), and normal B cells.
- To investigate potential differences in the origin and antigen-recognition pathways between HCL subtypes.
Main Methods:
- Analysis of immunoglobulin heavy chain gene rearrangements from 130 HCL patients (102 HCLc, 28 HCLv).
- Examination of SHM patterns, including mutation frequency, location (complementarity determining regions vs. framework regions), and hot spot usage.
- Comparison of SHM features between HCLc, HCLv, CLL, and normal B cells.
Main Results:
- HCLc showed a significantly lower frequency of unmutated rearrangements compared to HCLv and CLL.
- HCLc exhibited canonical SHM features (higher replacement/silent mutation ratio, elevated transition/transversion ratio, and increased hot spot mutations) similar to CLL.
- HCLv displayed less evidence of canonical SHM compared to HCLc and CLL, with a higher proportion of unmutated rearrangements.
Conclusions:
- HCLc B-cell receptors undergo antigen-driven selection, similar to CLL and normal B cells.
- HCLv B-cell receptors show distinct mutational patterns, suggesting a different origin possibly independent of antigen recognition.
- These findings highlight the heterogeneity within HCL and provide insights into the distinct pathogenetic mechanisms of HCL subtypes.
Abstract:
To compare hairy cell leukemia (HCL) with chronic lymphocytic leukemia (CLL) and normal B cells with respect to their B-cell receptors, somatic hypermutation (SHM) features in HCL were examined in a series of 130 immunoglobulin gene heavy chain rearrangements, including 102 from 100 classic (HCLc) and 28 from 26 variant (HCLv) patients. The frequency of unmutated rearrangements in HCLc was much lower than that in HCLv (17% vs 54%, P < .001) or historically in CLL (17% vs 46%, P < .001), but HCLv and CLL were similar (P = .45). As previously reported for CLL, evidence of canonical SHM was observed in HCLc rearrangements, including: (1) a higher ratio of replacement to silent mutations in the complementarity determining regions than in the framework regions (2.83 vs 1.41, P < .001), (2) higher transition to transversion ratio than would be expected if mutations were random (1.49 vs 0.5, P < .001), and (3) higher than expected concentration of mutations within RGYW hot spots (13.92% vs 3.33%, P < .001). HCLv met these 3 criteria of canonical SHM to a lesser extent. These data suggest that, whereas HCLc cells may recognize antigen-like CLL and normal B cells before malignant transformation, HCLv cells from some patients may originate differently, possibly without undergoing antigen recognition.
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