Haematologica
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Published online 2 April 2008
Haematologica, Vol 93, Issue 5, 697-705 doi:10.3324/haematol.12282
Copyright © 2008 by Ferrata Storti Foundation
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Lymphoproliferative Disorders

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

Francesco Forconi1, Elisa Sozzi1, Davide Rossi2, Surinder S. Sahota3, Teresa Amato4, Donatella Raspadori1, Livio Trentin5, Lorenzo Leoncini2, Gianluca Gaidano2, Francesco Lauria1

1 Sezione Ematologia e Trapianti, Università di Siena
2 Divisione di Ematologia, Dipartimento di Medicina Clinica e Sperimentale and Centro Interdisciplinare di Biotecnologie per la Ricerca Medica Applicata, Università del Piemonte Orientale Amedeo Avogadro, Novara, Italy
3 Cancer Sciences Division, University of Southampton, UK
4 Sezione di Anatomia Patologica, Università di Siena and
5 Dipartimento di Medicina Clinica e Sperimentale, Divisione di Ematologia-Immunologia, Università di Padova, Italy

Correspondence: Francesco Forconi, MD, DM, PhD, Sezione di Ematologia e Trapianti, Dipartimento di Medicina Clinica e Scienze Immunologiche, Università di Siena, AOUS, viale Bracci, 53100 Siena, Italy E-mail: forconif{at}unisi.it

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.

Design and Methods: To further investigate this issue, we examined the full IGH and {kappa} and {lambda} light chains (IG{kappa} and IG{lambda}) 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 Ig{lambda} 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.

Key words: hairy cell leukemia, immunoglobulin, IGH, IGL, IGK, heavy chain, light chain.






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