Heterogeneous somatic hypermutation status confounds the cell of origin in hairy cell leukemia

Hair cell leukemia (HCL) is thought to arise from a post-germinal center (GC) B-cell, however the exact normal counterpart remains unclear. We performed V-H gene analysis of 32 HCL cases, revealing somatically mutated V-H genes (<98% homology) in 27 cases and unmutated V-H genes in five cases, four of which displayed germline V-H genes. Intraclonal heterogeneity was evident in the majority of eight Mutated HCLs investigated, although at a lower level compared to GC-derived lymphomas. A novel finding of preferential V(H)3-30 gene usage was detected (19% of HCLs). Our data confounds the postulated post-GC origin in HCL considering (1) the finding of unmutated HCLs. generally correlating with a pre-GC origin, and (2) the presence of intraclonal variation in mutated HCLs. The latter suggests that the transformed B-cell was frozen when it still had all active mutation process, implying a closer relation to the GC than previously assumed. Furthermore, restricted V(H)3-30 usage indicates that antigen Selection Could be a promoting factor in HCL development. (C) 2004 Elsevier Ltd. All rights reserved.