Identification of three subgroups of B cell chronic lymphocytic leukemia based upon mutations of BCL-6 and IgV genes

Although B cell chronic lymphocytic leukemia (B-CLL) has been traditionally viewed as a tumor of virgin B cells, this notion has been recently questio ned by data suggesting that a fraction of B-CLL derives from antigen experi enced B cells. In order to further clarify the histogenetic derivation of t his lymphoproliferation, we have analyzed the DNA sequences of the 5' non-c oding region of BCL-6 proto-oncogene in 28 cases of B-CLL. Mutations of BCL -6 proto-oncogene, a zinc finger transcription factor implicated in lymphom a development, represent a histogenetic marker of B cell transit through th e 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 analyz ed for somatic mutations of the rearranged immunoglobulin variable (IgV) ge nes, which are known to be acquired at the time of B cell transit through t he GC. Sequence analyses of BCL-6 and IgV genes allowed the definition of t hree groups of B-CLL, Group I B-CLL displayed mutations of both BCL-6 and I gV genes (10/28; 36%). Group II B-CLL displayed mutated IgV genes, but a ge rmline BCL-6 gene (5/28; 18%). Finally, group III B-CLL included the remain ing cases (13/28; 46%) that were characterized by the absence of somatic mu tations 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 histogen etically heterogeneous and that a substantial subgroup of these lymphoproli ferations derives from post-germinal center B cells.