SUMMARY REMARKS ON THE DEVELOPMENT, GROWTH, AND EVOLUTION OF B-CLL
On the basis of the foregoing information, we propose a model for the development of B-CLL. B-CLL cells are able to avoid apoptosis and even to proliferate by receiving growth and stimulatory signals from the environment delivered through their BCR or other receptors; these signals likely involve autologous and foreign antigens, cytokines, and chemokines, as well as yet-to-be-defined ligand on accessory and stromal cells. The cell’s BCR mediates major growth effects in cases for which the receptor is polyreactive, binding autoantigens and foreign antigens, while maintaining its capacity to transmit stimulatory signals to the cell nucleus. Both self-reactivity and intact BCR signal-transducing capacity are more frequently found in U-CLL;hence, the more active clonal expansion and clinical aggressiveness of patients with such clones.
These considerations are in line with the results of in vivo labeling experiments that involve incorporation of nonradioactive deterium into newly synthesized DNA of dividing cells. These studies have shown B-CLL clones to be dynamic, having measurable birth rates from about 0.1 to>1.0 percent of the clone/day. Although only a minority of cells in a B-CLL clone can be shown to divide using this approach, estimates of the leukemic cell burden of typical B-CLL patients are of the order of about 10(12) cells, and therefore about 10(9) to 10(10) new leukemic cells would be generated daily. Such rates of cell division are sufficient to permit more dangerous clonal variants to emerge and to influence clinical course and outcome over time.
Similarly, there is a rough correspendence between the clinical course of patients and the development of chromosomal abnormalities in their clones. Recurrent chromosomal lesions typically found in B-CLL patients include deletion at 13q14.3,11q22-23,17p13, and 6q21, and amplifications of all or portions of chromosome 12. Deletion at 13q14.3 is found in greater than half of B-CLL cases over time and is linked to loss of two micro-RNAs that can regulate Bcl-2 expression. However, thus particular chromosomal abnormality is not especially dangerous because patients exhibiting this deletion on one allele and no other DNA lesions in their clones have a clinical course that is benign and comparable to normal age-stratified individuals. In contrast, deletions at 11q22-23, 17p13, and 6q21 are generally associated with more aggressive disease, perhaps because these deletions may affect important genes such as p53 (17p13 deletion), and ataxia telangiectasia mutated (ATM; 11q22-23 deletion). Longitudinal studies, albeit on a relatively limited number of patients, demonstrated that these ominuous cytogenetic abnormalities accumulate progressively in the course of the disease and more frequently in patients with U-CLL.
CORRELATIONS BETWEEN THE CELLULAR AND MOLECULAR FEATURES OF THE DISEASE WITH THE CLINICAL COURSE OF B-CLL
How might features of the repertoire of IgVH genes used by B cells in B-CLL, the mutations status of these genes, and expression of molecules related to cellular activation and BCR signal transduction (CD38 and ZAP-70) be relevant to the clinical course of B-CLL? These disease manifests differently in different patients, depending on the utilization of mutated or unmutated IgVH genes and the expression of ZAP-70 and CD38 by the leukemic cells. One explanation is that activation via the BCR following recognition of (self) antigens activates the cells in vivo, accompanied by expression of CD38 and ZAP-70. Because the majority of U-CLL clones contain a self-reacting BCR, while most M-CLL clones do not, it is not unexpected that more activation markers are found on U-CLL cells. In addition, B-CLL clones from patients in different prognostics subsets differ in signaling capacity, with an intact BCR signal transductions pathway found most frequently among patients exhibiting unfavorable prognostic markers. Thus, continuous (auto)antigenic stimulation would likely represent a major factor for U-CLL cases and much less likely for M-CLL.
In addition to antigen stimulation, B-CLL cells also receive receptor-mediated signals as well as soluble factors, such as cytokines and chemokines, from other lymphoid and nonlymphoid cells. In particular, it is thought that in vivo B-CLL cell interactions with stromal cells and “nurselike” cells can rescue normally (ex vivo) apoptosis-prone B-CLL cells from death. The natural ligand of CD38, CD31, is displayed on stromal and nurselike cells as well as on endothelial cells and might be involved in setting up these rescue signals. Such contact derived and soluble signals can go on to up-regulate anti-apoptotic genes, such as Bcl-2, survivin, and Mcl-1, which could rescue B-CLL cells from apoptosis and fascilitate their growth.
A hypothesis such as this implies that it might be possible to detect clonal expansions in healthy subjects. In fact, small numbers of apparently clonal B cells with B-CLL cell characteristics do exist in the blood of about 3.5% of disease-free individuals. An even higher proportion of such clones have been found in the blood of first-degree relatives of patients with B-CLL (as often as 12%). Although such studies of the BCRs of B lymphocyte expansions in normal disease-free individuals are limited, they further support this hypothesis in that these expansions are not only monoclonal but also use some of the same genes commonly encoding the BCRs of B-CLL clones.
With continued expansion leading (or not) to accumulation of IgVH gene mutations as explained by the T-cell-dependent versus T-cell-independent models mentioned earlier, it becomes increasingly likely that a cell develops a genetic abnormality as in an initial inducing lesion that would lead to relatively unrestrained expansion. Such a cell is primed for leukemic transformations.