Micromanagement of lymphomas.

Lymphomas are tumours composed of lymphocytes. The two types of lymphocytes—T cells and B cells—are distinguished by the antigen receptors on their surfaces and the specific functions they undertake on behalf on the immune system. Precursors of B cells are generated in the bone marrow and leave only after they have undergone a genetic rearrangement of the DNA encoding the protein chains that compose the functional B cell receptor (BCR). Each BCR binds a specific antigen, and if it is a foreign antigen (i.e., from an invading pathogen), that specific B cell undergoes division to produce many identical progeny (clonal amplification) that will later produce antibodies, which are the secreted form of the BCR present on the cell surface. Normal pre-B lymphocytes are developmentally programmed to undergo apoptosis (Bcl-2 gene expression, which results in survival, is down-regulated in these cells). However, the expression of a functional BCR leads to signalling that up-regulates Bcl-2 expression and rescues these cells such that they relocate in the peripheral blood and become mature B cells [1–4]. Therefore, during development, B cells are continuously under selective pressure to express functional BCRs. This implies the existence of a basic BCR-mediated signal that provides maintenance of the B cell homeostasis [5]. The nature of this constitutive signal is distinct from an antigen-driven signal that leads to proliferation and clonal expansion of the mature B cells, and therefore it is better defined as a basal, or “tonic”, signal [6–8]. However, a mechanistic understanding of this survival tonic signal is still lacking. Perhaps B cells require constitutive low-level receptor engagement with low-affinity autoantigens for survival [9]. Conversely, the tonic signal could be the result of a steady-state level of signalling in unstimulated cells, generated by an equilibrium between positive and negative regulators downstream of the BCR [8]. Certainly, the specific signalling pathway initiated by the BCR to sustain pre-B cells is still elusive, and it remains debatable whether the receptor signals autonomously or requires activation by antigen.