The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms.

Follicular lymphoma (FL) and B-cell chronic lymphocytic leukemia (B-CLL) are paradigmatic examples of lymphoid malignancies in which the relevant biological mechanisms are alterations in the control of apoptosis rather than an exaggerated proliferation. This explains why low-grade B-cell neoplasms still fail to be cured with current approaches. It is becoming increasingly clear that the defective apoptosis of FL and B-CLL has to be ascribed not only to intrinsic defects of the neoplastic cells, but also to extrinsic factors that influence their behavior. Malignant B cells retain the capacity to respond to microenvironmental signals, but have devised a monothematic responsiveness. They have a specific sensitivity to anti-apoptotic signals that favor their survival, whereas they seem to have become insensitive to pro-apoptotic signals. Bystander, nontumoral cells play a fundamental (though not sufficient) role both in the onset and in the progression of these diseases. The survival of leukemic cells appears to be dependent on direct cell-cell contacts. The localization of malignant B cells in bone marrow or neoplastic follicles is not a passive adhesion phenomenon but a crucial step for their survival. Bidirectional malignant lymphocyte-nontumoral cell interactions may lead to the amplification of a microenvironment able to inhibit the apoptosis of neoplastic B cells. The pressure of antigenic selection and the role of the tumor necrosis factor receptor family through the functional survival signal provided by CD40 together with the crippled death signal exerted by CD95 are new prominent characters on the stage.