CHRONIC LYMPHOCYTIC-LEUKEMIA B-CELLS EXPRESS RESTRICTED SETS OF MUTATED AND UNMUTATED ANTIGEN RECEPTORS

To better understand the stage(s) of differentiation reached by B-type chronic lymphocytic leukemia (B-CLL) cells and to gain insight into t he potential role of antigenic stimulation in the development and dive rsification of these cells, we analyzed the rearranged V-H genes expre ssed by 83 B-CLL cells (64 IgM(+) and 19 non-IgM(+)). Our results conf irm and extend the observations of a bias in the use of certain V-H, D , and J(H) genes among B-CLL cells. In addition, they indicate that th e V-H genes of similar to 50% of the IgM(+) B-CLL cells and similar to 75% Of the non-IgM(+) B-CLL cells can exhibit somatic mutations. The presence of mutation varies according to the V-H family expressed by t he B-CLL cell (V(H)3 expressers displaying more mutation than V(H)1 an d V(H)4 expressers). In addition, the extent of mutation can be sizeab le with similar to 32% of the IgM(+) cases and similar to 68% of the n on-IgM(+) cases differing by > 5% from the most similar germline gene. Approximately 20% of the mutated V-H genes display replacement mutati ons in a pattern consistent with antigen selection. However, CDR3 char acteristics (D and J(H) gene use and association and HCDR3 length, com position, and charge) suggest that selection for distinct B cell recep tors (BCR) occurs in many more B-CLL cells. Based on these data, we su ggest three prototypic BCR, representing the V-H genes most frequently encountered in our study. These data suggest that many B-CLL cells ha ve been previously stimulated, placing them in the ''experienced'' or ''memory'' CD5(+) B cell subset.