Somatic hypermutation and VH gene usage in hairy cell leukaemia

Abstract

SummaryTo examine the usage and mutational status of VH genes in hairy cell leukaemia (HCL), we analysed 24 immunoglobulin heavy chain (IgH) sequences expressed in 23 patients. None had premature stop codons. VH3-23 was the most common gene and a VH6 gene was observed for the first time in HCL. Although the mean mutation frequency was 6AE1%, slightly higher than in previous HCL series, four patients had 99AE6-100% homology to germline sequences, three of whom had high tumour burdens and poor outcomes. Despite the high mutation frequency, only two of 24 rearrangements had clear statistical evidence of antigen-dependent somatic mutation. Our results increase the database of reported functional HCL rearrangements to 94 in 92 patients. Overall, both gene usage and mutation frequency are very similar to mucosa-associated lymphoid tissue-type marginal zone lymphoma. The data are consistent with HCL originating from post-germinal centre marginal zone B cells, although the heterogeneity observed suggests that HCL may originate differently in some patients, and this could have implications for prognosis and treatment.

Selective influences in the expressed immunoglobulin heavy and light chain gene repertoire in hairy cell leukemia

“…36 Clearly, the selective influences active in HCL appear to follow routes that are different from those of other B-cell neoplasms, in particular from the extensively investigated IgMpositive chronic lymphocytic leukemia (CLL). 19 For example, IGHV1-69 was totally absent in HCL from our and previously published series (total 164 IgHV sequences), 2,7,8,21,22,37 while it dominates the unmutated subset in CLL (Online Supplementary Figures S1A and S1B). 19 Similarly, IGHV4-34 is used predominantly in a mutated conformation by CLL, but was preferentially unmutated in the HCL cases in our series ( Figure 5A), and even more significantly when all published HCL sequences were pooled (p=0.0002).…”

“…19 Similarly, IGHV4-34 is used predominantly in a mutated conformation by CLL, but was preferentially unmutated in the HCL cases in our series ( Figure 5A), and even more significantly when all published HCL sequences were pooled (p=0.0002). 2,7,8,21,22,37 Lack of apparent HCDR3 stereotypy in HCL is another feature of variance with CLL, which, conversely, frequently groups cases with shared HCDR3 structural features. 4,18,38 This also indicates that antigen drive may not rely on HCDR3-mediated interactions in HCL.…”

“…However, the number of sequences investigated (n=69) here and the few HCDR3 currently available in the literature (n=27) preclude any statistical clustering. 8,22,23 Thus, the significance of IGHD biases remains unresolved as yet.…”

“…However, by combining results of this study with those of all published HCL IGHV gene sequences (n=164, Online Supplementary Figure S1A), we confirmed the overuse of IGHV3-21, IGHV3-30 and IGHV3-33, and demonstrated the significantly reduced use of IGHV1-18 (p=0.02) and IGHV3-53 (p=0.02). 8,9,21,22 Phenotypic analysis of surface IgM, IgD, IgG and IgA was performed in 56 HCL (Online Supplementary Table S1). The majority (46/56, 82%) co-expressed multiple pre-(IgM±D) and post-switch (IgG±A) isotypes, indicating that multiple isotype expression is a dominant feature in HCL.…”

The Heavy Chain Variable Segment Gene Repertoire in Chronic Chagas′ Heart Disease

“…Analyzed VH genes were considered mutated using a 98% germline homology cut off as described by Kienle et al (39) and Arons et al (40). All analyzed VH genes were mutated, with the exception of three VH genes from the patient repertoire that presented 98% homology to the corresponding germline genes.…”