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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 (Figure 7.6).
Figure 7.6 Model to explain the development and evolution of B-CLL. See text for description. Reprinted with permission from Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804–815.
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 for-eign antigens, cytokines, and chemokines, as well as yet-to-be-defined ligands 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 stimu-latory signals to the cell nucleus. Both self-reactivity and intact BCR signal-transduc-ing capacity are more frequently found in U-CLL; hence, the more active clonal expansion and clinical aggressiveness of patients with such clones.
Because in vitro observations demon-strate the absence of lesions in the major apoptotic pathways, our model posits the absence of an intrinsic cell death defect in the majority of the leukemic clones. We do not rule out the possibility that developing genetic alterations in the evolving clone can tip the balance between pro- and anti-apoptotic molecules in such a way as to favor B-CLL cell survival. However, the influence of external signals appears to dominate based on current knowledge. This is in line with the in vivo labeling studies indicating the dynamic nature of CLL clones.
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