The Normal IGHV1-69-derived B Cell Repertoire Contains “Stereotypic” Patterns Characteristic of Unmutated CLL.

Abstract 4370

The cell of origin of chronic lymphocytic leukemia (CLL) has long been sought and immunoglobulin gene analysis provides new clues. The immunoglobulin heavy variable gene (IGHV) status has clinical relevance in CLL, where two subsets, delineated by the absence or presence of somatic mutation, have markedly different prognoses. The unmutated subset (U-CLL), of inferior prognosis, appears to derive from a pre-germinal center B cell. In U-CLL, there is strikingly increased usage of the 51p1-related alleles of the IGHV1-69 gene, often combined with selected IGHD genes and with IGHJ6. Shared sequence “stereotypic” characteristics of the HCDR3 result, and suggest antigen selection of the leukemic clones. In this study, we have analyzed 147 51p1/IGHJ6 rearrangements from 3 healthy individuals (>51yr) and sought sequence patterns parallel to those of U-CLL. A pre-established dataset of 313 51p1/IGHJ6 rearrangements from patients with U-CLL was used as a reference. A high proportion (49/147, 33.3%) of normal sequences revealed stereotypic patterns, several (22/147, 15%) being similar to those described in U-CLL. Additional CLL-associated stereotypes, not yet reported, were detected in 7/147 sequences (4.8%). Stereotypes (13.6%) not detected in CLL were also found in 20/147 (13.6%) 51p1/IGHJ6 combinations. The HCDR2-IGHJ6 sequences were almost exclusively unmutated (143/147, 97,3% sequences had ≥98% homology to germline). Junctional amino acids in normal B cells were heterogeneous, as in the cases of CLL with stereotyped 51p1/IGHJ6 B-cell receptors. Normal B cells expressing 51p1-derived IgM (4.8% of all B-cells) had a phenotype of naïve B-cells, similar to 51p1-negative (CD27-) B cells, i.e. IgM+ IgD+ CD23+ CD38+, with a small percentage of CD5+ B cells, not found in the memory B-cell subset. This snapshot of the naïve B-cell repertoire reveals subsets of B cells closely related to those characteristic of CLL. Conserved patterns in the 51p1-encoded IgM of normal B cells suggest a restricted sequence repertoire shaped by evolution to recognize common pathogens. Proliferative pressure on these cells is the likely route to U-CLL.