Neoplastic development ie B-Iymplhocytes

Neoplastic transformation is a complex process that results from multiple changes in gene activities. Probably most of these are mutational, i.e. alterations in the genomic structure of DNA, but others may be due to adaptive changes wherein genes are expressed that are inappropriate to a stage of development or differentiation. In this commentary neoplastic development is discussed in the context of a single differentiation (B-lymphocyte) lineage. A challenging problem in neoplastic development is to define changes in gene activities in biochemical and genetic terms. There is a network of genes whose products control the cell division cycle and the proliferation of cells. A problem is to interpret how oncogenic mutations disrupt this process and create the phenotype of autonomous growth. The question varies with different tissues which have different modes of cell proliferation activities that are controlled by tissue-specific factors. Much of the emphasis in this commentary is given to mutational mechanisms, partly because so many examples have been recently discovered. There should be some caution though in attempting to explain all of neoplastic development and progression in mutational terms. The development of several different tumors in fixed tissues provides some evidence for the role of adaptive changes in tumorigenesis (see discussions in refs 1-3). Many of these are caused by a disruption of the organization of a fixed tissue which requires adaptation of cells to new conditions. There are other mechanisms for altering gene expression as discussed by Holliday and Jeggo (3) that do not involve altering the primary structure of DNA, e.g. alterations in DNA methylation. Essentially the underlying concept of adaptation is that genes inappropriate to the stage of development or even differentiation are activated. Physiological adaptation is more difficult to assess in hematopoietic tissues where the cells normally are free and only loosely attached to other cells and continuously expended and replaced. But there may be forms of physiological adaptation that occur in these populations that we do not recognize easily. Examples might be the (autocrine) secretion of a growth factor or the inappropriate expression of a receptor. Possibly the development of some mutations may trigger a series of cryptic adaptations.