¹Division of Internal Medicine, Department of Medical Sciences, 'Amedeo Avogadro' University of Eastern Piedmont, Novara, USA

²Servizio di Immunologia Clinica, Istituto Nazionale per la Ricerca del Cancro, Genoa, USA

³Department of Oncology, Biology and Genetic, University of Genoa, Genoa, USA

⁴Division of Epidemiology, Department of Medical Sciences, 'Amedeo Avogadro' University of Eastern Piedmont, Novara, USA

⁵Department of Medicine of North Shore University Hospital and NYU School of Medicine, Manhasset, NY, USA

Correspondence to: M Ferrarini, Servizio di Immunologia Clinica, Istituto Nazionale per La Ricerca sul Cancro, IST, Largo Rosanna Benzi, n. 10, 16132 Genova GE, Italy; Fax: +39 010 5600 264

^aThese authors contributed equally to this work

Although B cell chronic lymphocytic leukemia (B-CLL) has been traditionally viewed as a tumor of virgin B cells, this notion has been recently questioned by data suggesting that a fraction of B-CLL derives from antigen experienced B cells. In order to further clarify the histogenetic derivation of this lymphoproliferation, we have analyzed the DNA sequences of the 5' non-coding region of BCL-6 proto-oncogene in 28 cases of B-CLL. Mutations of BCL-6proto-oncogene, a zinc finger transcription factor implicated in lymphoma development, represent a histogenetic marker of B cell transit through the germinal center (GC) and occur frequently in B cell malignancies derived from GC or post-GC B cells. For comparison, the same tumor panel was analyzed for somatic mutations of the rearranged immunoglobulin variable (IgV) genes, which are known to be acquired at the time of B cell transit through the GC. Sequence analyses of BCL-6 and IgV genes allowed the definition of three groups of B-CLL. Group I B-CLL displayed mutations of both BCL-6 and IgV genes (10/28; 36%). Group II B-CLL displayed mutated IgV genes, but a germline BCL-6 gene (5/28; 18%). Finally, group III B-CLL included the remaining cases (13/28; 46%) that were characterized by the absence of somatic mutations of both BCL-6 and IgV genes. Overall, the distribution of BCL-6 and IgV mutations in B-CLL reinforce the notion that this leukemia is histogenetically heterogeneous and that a substantial subgroup of these lymphoproliferations derives from post-germinal center B cells. Leukemia (2000) 14, 811-815.

chronic lymphocytyc leukemia; BCL-6; immunoglobulin variable region; somatic mutation