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

Abstract

BackgroundWe previously reported ongoing mutational and isotype switch events in the immunoglobulin (Ig) heavy chain (H) locus in hairy cell leukemia. Those analyses raised questions on the incidence and type of selective influences occurring on the tumor B-cell receptor of hairy cell leukemia.

Defining origins of malignant B cells: a new circulating normal human IgM+D+ B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population

“…We had previously shown that IgM-expressing HCL displayed mutated IGHV genes yet lacked CD27, and frequently co-expressed multiple switched isotypes (mult-HCL). 4,5,11 Our large cohort study had shown that mult-HCLs comprised the major subset of disease, as compared with single isotype-expressing HCL. 4 It is conceivable that IgM-co-expressing mult-HCL derives from the novel mutated IgM þ D þ CD27 Àve B cells described in this study.…”

“…4,5,11 Our large cohort study had shown that mult-HCLs comprised the major subset of disease, as compared with single isotype-expressing HCL. 4 It is conceivable that IgM-co-expressing mult-HCL derives from the novel mutated IgM þ D þ CD27 Àve B cells described in this study. mult-HCL tumor cells also initiate atypical switch events, which seem to exclude deletional class switch recombination and generate variant isotype transcripts most likely through RNA processing.…”

“…4,7,11 PCR products were cloned and individual plasmids with IGHV-IGHM inserts were sequenced as described. 4,7,11 Taq error was calculated in a 350-400 bp stretch of the IGHM constant region (excluding primer sequences) using semi-nested IGHV5 or IGHV3 upstream primers, as described above, with IGHM370 (5 0 -tggacttgctgcgggggttg) or IGHM430 (5 0 -ggacacctgaatctgccg). Data analysis, using Immunogenetics (IMGT) databases, 12 is based on pooled clones obtained from replicate PCRs.…”

“…This is illustrated by hairy cell leukemia (HCL) cells that exhibit mutated IGHV genes but are CD27 Àve . 4,5 In addition, in IgM-expressing Waldenstrom's macroglobulinemia, mutated tumor cells are seen in CD27 Àve fractions, 6,7 and it has been proposed that origins of this disease may be from 'unusual' memory B cells. 6 Interestingly, more recent observations indicate that the normal human B-cell memory pool may as yet not be mapped fully.…”

Higher expression levels of activation-induced cytidine deaminase distinguish hairy cell leukemia from hairy cell leukemia-variant and splenic marginal zone lymphoma

“…6 These results are also in line with the reports of existence of ongoing SHM in HCL cases with mutated IGHV, including those with less than 2% mutations, and also with the production of germline immunoglobulin heavy chain (IgH) transcripts that occur before deletional CSR and coincide with the expression of multiple IgH isotypes in this disorder. 9 Although high AICDA expression in HCL could be interpreted as evidence of a GC origin for this disorder, it has been shown that the HCL gene expression signature most closely resembles that of memory rather than GC B cells. 10 We and others have postulated that transformation of HCL, as well as that of HCL-variant and SMZL, occurs at sites capable of undergoing SHM independent of GC formation.…”