Abstract
Recognition of biased immunoglobulin variable (IgV) gene usage in B-cell chronic lymphocytic leukemia (B-CLL) may yield insight into leukemogenesis and may help to refine prognostic categories. We explored Ig variable heavy (VH) and light (VL) chain gene usage in highly stable and indolent B-CLL (n=25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated VH3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; P<0.01), including mutated cases (6/432; 1.39%; P<0.01) and was exceptional among indolent (1/230, 0.435%; P<0.01), and aggressive B-cell lymphomas (0/105; P<0.01). Three of six VH3-72 B-CLL cases utilized the same VL Vκ4-1 gene. Two VH3-72 B-CLL cases had highly homologous VH complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized Vκ4-1 genes with homologous IgVL CDR3s. An identical threonine to isoleucine change at codon 84 of VH3-72 framework region 3 (FR3) recurred in four cases of highly stable VH3-72 B-CLL. This mutation is expected to cause a conformational change of FR3 proximal to CDR3 that might critically affect high-affinity antigen binding. B-cell receptors encoded by VH3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.
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Acknowledgements
This study has been supported by Progetto Strategico Oncologia, CNR-MIUR, Rome, Italy; Cofin 2002 – MIUR, Rome, Italy; Ricerca Finalizzata 2002, Ministero della Salute, Rome, Italy; Regione Piemonte, Torino, Italy; Novara-AIL Onlus, Novara, Italy; and Associazione Italiana per la Ricerca sul Cancro (AIRC), Milano, Italy. EB has been supported by Fondazione ‘Piera Pietro Giovanni Ferrero’, Alba, Italy.
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Capello, D., Guarini, A., Berra, E. et al. Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia. Leukemia 18, 1941–1947 (2004). https://doi.org/10.1038/sj.leu.2403537
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DOI: https://doi.org/10.1038/sj.leu.2403537