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


METHODS
To further investigate this issue, we examined the full IGH and kappa and lambda light chains (IGkappa and IGlambda) variable and constant region transcripts expressed in a large cohort of patients with hairy cell leukemia (n=88).


RESULTS
Multiple IgH isotypes were expressed in 46/56 (82%) cases of hairy cell leukemia. Comparison of tumor with normal B-cell repertoires revealed preferential usage of IGHV3-21, IGHV3-30 and IGHV3-33 in hairy cell leukemia (p=0.001, p=0.003 and p=0.001, respectively). Light chain analysis demonstrated preferential Igl use with an inverted IGk:IGl ratio (0.7:1) and universal usage of IGLJ3. Analysis of LCDR3 junctions revealed highly homologous motifs in 40% of IGL. Parallel analysis of IGH and IGL showed selective pairing of IGHV3-21/30/33 segments to specific LCDR3-J3 subsets (p=0.008). Of 40 cases of hairy cell leukemia, 38 had mutated IGHV and/or IGK/LV, with variations in 13/13 cloned cases, while two had 100% unmutated IGHV and IGK/LV.


CONCLUSIONS
Overall, biased IGV usage, preference for Iglambda with universal IGLJ3 usage and a high incidence of LCDR3 homologous motifs suggest selective influences on the B-cell receptor of hairy cell leukemia. Ongoing mutations and isotype switching suggest that influences occur on the tumor B-cell receptor at ectopic sites.
Forconi
Francesco
F
DM, Sezione di Ematologia e Trapianti, Dipartimento di Medicina Clinica e Scienze Immunologiche, Università di Siena, AOUS, viale Bracci, 53100 Siena, Italy. forconif@unisi.it
Sozzi
Elisa
E
Rossi
Davide
D
Sahota
Surinder S
SS
Amato
Teresa
T
Raspadori
Donatella
D
Trentin
Livio
L
Leoncini
Lorenzo
L
Gaidano
Gianluca
G
Lauria
Francesco
F
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism; D004252:DNA Mutational Analysis; D015973:Gene Expression Regulation, Leukemic; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000235:genetics*; D016130:Immunophenotyping / Q000379:methods; D007943:Leukemia, Hairy Cell / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains