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

• 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 VH gene analysis of 32 HCL cases, revealing somatically mutated VH genes (<98% homology) in 27 cases and unmutated VH genes in five cases, four of which displayed germline VH 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 VH3-30 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 VH3-30 usage indicates that antigen selection could be a promoting factor in HCL development.

Nyckelord

Adult

Aged

Aged; 80 and over

Base Sequence

Female

Gene Rearrangement; B-Lymphocyte; Heavy Chain

Humans

Immunoglobulin Heavy Chains/analysis/*genetics

Leukemia; B-Cell/genetics/immunology/pathology

Leukemia; Hairy Cell/*genetics/immunology/pathology

Male

Middle Aged

Molecular Sequence Data

Research Support; Non-U.S. Gov't

Somatic Hypermutation; Immunoglobulin/*genetics

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