The continuing search for the cell of origin of chronic lymphocytic leukemia

For long time, chronic lymphocytic leukemia (CLL) has been considered to be a clonal accumulation of immature, immuneincompetent B lymphocytes which accumulate in the body mainly because of a faulty apoptotic apparatus. Numerous recent findings have contributed to a change in this classical credo.1-3 CLL is now viewed as a disease of antigen experience B cells, which have proliferated and possibly continue to do so in response to an antigenic stimulus in some instances even following the final transforming events. Several findings, which take place, have contributed to the formulation of this hypothesis, including the impossibility of detecting lesions in the cell apoptotic apparatus,4 the studies on telomeres length of the neoplastic cells,5 which demonstrated shorter telomeres than in normal antigen- inexperienced B cells, and the cell turn-over studies using deuterium to label the cell nucleic acids.6 The latter studies have demonstrated that CLL cells have a rather rapid turn-over characterized by active cell proliferation and death. This turn-over may be different in different patients and in general is more active in those patients whose cells utilize unmutated VDJ gene segments and express CD38 and ZAP-70. Altogether, the latter findings also raise the question of whether CLL is an homogeneous disease entity, or whether it should be considered as being comprised of two different pathological conditions, one (the unmutated CLL) with a rather aggressive clinical course and outcome related to a more active and invasive clonal expansion and the other (mutated CLL) with a more indolent clinical course and the tendency not to progress towards the more advanced clinical stages. Here, we shall review the immunologic features of the neoplastic cells, including some facts and speculations on the possible encounters with antigen. Based on this and other information, we shall try to indicate the potential progenitor cell of the CLL. Central to this question is also the issue of whether one or more cell types can generate CLL clones.