Figure 2.

Progressive and indolent CLL landscapes based on microenvironmental influences. In patients with progressive disease, an activated microenvironment continuously nourishes leukemic cells by maintaining proliferative fractions that can express AID. Proliferating cells overexpressing AID are susceptible to novel DNA lesions (many of them in non-Ig genes), establishing clonal and subclonal entities before and/or after treatment. These can lead to CLL progression and/or therapy resistance. Some of the leukemic cells dividing in proliferation centers leave the tissues and move into the blood. These circulating cells must return to lymphoid tissues to receive survival signals. If not, they eventually die. Cycles of these two events overtime lead to increased numbers of circulating AID⁺ leukemic B cells, which is a hallmark of progressive CLL. In patients with indolent disease, microenvironmental signaling is similar to that taking place in normal GCs, with CLL cells becoming physiologically activated and AID expression and non-Ig genes mutations being better controlled.