In the September issue of Blood is a useful review of CD38 by Fabio Malavasi from Turin. I will be taking it to pieces in the next few days and weeks to make it available to a lay audience.
Currently we view CLL as a disease with a balance between cells in the blood and cells in the lymphoid organs. The former are primarily mature-looking small lymphocytes resistant to apoptosis (programmed cell death), whereas the latter are composed of lymphocytes that undergo either proliferation or apoptosis according to the environment.
The varying clinical outcome of CLL patients is dictated, at least in part, by the nature of these microenvironmental signals and interactions that can promote or impair accumulation of genetic alterations. Detailed immunophenotypic and genetic analyses of different neoplastic clones have led to the identification of a number of molecular markers, some of which are gaining relevance in clinical practice to predict disease outcome. Cell surface CD38 is one of these markers. It is generally accepted that CD38+ patients will have a shorter progression-free interval, require earlier and more frequent treatments, and ultimately die sooner.
The most obvious explanation for the ill-effect of CD38 expression is that it reflects events occurring inside the cell. Indeed, the percentage of CD38+ cells within a leukemic clone was originally described as one of two independent indicators (along with IGHV gene mutations) of clinical outcome in CLL. Because both indicators marked somewhat overlapping populations, a link with IGHV mutation status, signals mediated by B-cell receptor (BCR), and CD38 was proposed but these two parameters are not obligatorily linked: and an alternative (and not mutually exclusive) hypothesis is that the presence of cell surface CD38 provides a bridge to the environment, shifting the balance between survival/proliferation and apoptosis in favor of the former. Evidence sustaining this idea has been collected over the past decade and has contributed to the formulation of the current concept of CLL as a chronic disease in which the patient physiologically provides essential elements and conditions leading to the acquisition and accumulation of genetic alterations by the leukemic cells.
These changes begin at a preneoplastic stage (ie, monoclonal B-cell lymphocytosis), or possibly even before, and continue to occur in a clone that progresses to a full-fledged CLL. This scheme accommodates the existence of structures that provide replicating and surviving signals to B cells on their way to neoplastic transformation. A key element in this view is that leukemic B cells can and do proliferate, with division taking place not in the blood, but primarily in specialized morphologically discrete structures of lymph nodes (LN) and bone marrow (BM) known as proliferation centers (PCs).
Different sets of molecules may have different roles and confer at times the ability to localize in privileged sites, to receive signals from the external environment, to undergo apoptosis, or to modify surrounding cells. In this context, evidence so far uncovered on the role of CD38 expression provides new depth and relevance about the regulation of the social life of the neoplastic B cell. In future articles the authors will explore the available evidence providing a mechanistic link between CD38 expression and CLL progression.