Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors.

TLDR

The study aimed to determine the differentiation stage of B‑CLL cells and assess the role of antigenic stimulation by analyzing VH gene rearrangements in 83 B‑CLL samples. The authors examined VH gene usage and somatic mutation patterns in 64 IgM+ and 19 non‑IgM+ B‑CLL cells, identifying three prototypic BCRs based on the most frequent VH genes. The analysis revealed a biased usage of VH, D, and JH genes, with 50 % of IgM+ and 75 % of non‑IgM+ B‑CLL cells harboring somatic mutations—particularly in VH3 families—and 20 % of mutated VH genes showing antigen‑selection signatures, indicating that many B‑CLL cells are antigen‑experienced memory CD5⁺ B cells.

Abstract

To better understand the stage(s) of differentiation reached by B-type chronic lymphocytic leukemia (B-CLL) cells and to gain insight into the potential role of antigenic stimulation in the development and diversification of these cells, we analyzed the rearranged VH genes expressed by 83 B-CLL cells (64 IgM+ and 19 non-IgM+). Our results confirm and extend the observations of a bias in the use of certain VH, D, and JH genes among B-CLL cells. In addition, they indicate that the VH genes of approximately 50% of the IgM+ B-CLL cells and approximately 75% of the non-IgM+ B-CLL cells can exhibit somatic mutations. The presence of mutation varies according to the VH family expressed by the B-CLL cell (VH3 expressers displaying more mutation than VH1 and VH4 expressers). In addition, the extent of mutation can be sizeable with approximately 32% of the IgM+ cases and approximately 68% of the non-IgM+ cases differing by > 5% from the most similar germline gene. Approximately 20% of the mutated VH genes display replacement mutations in a pattern consistent with antigen selection. However, CDR3 characteristics (D and JH gene use and association and HCDR3 length, composition, and charge) suggest that selection for distinct B cell receptors (BCR) occurs in many more B-CLL cells. Based on these data, we suggest three prototypic BCR, representing the VH genes most frequently encountered in our study. These data suggest that many B-CLL cells have been previously stimulated, placing them in the "experienced" or "memory" CD5(+) B cell subset.