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

Abstract 

Hairy 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_H3-30 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 an active mutation process, implying a closer relation to the GC than previously assumed. Furthermore, restricted V_H3-30 usage indicates that antigen selection could be a promoting factor in HCL development.

Keywords: Hairy cell leukemia, Immunoglobulin genes, V_H genes, Somatic hypermutation status, Intraclonal heterogeneity