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-6 
proto-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.