The chronic lymphocytic leukemia microenvironment: Beyond the B-cell receptor

Malignant B cells accumulate in the peripheral blood, bone marrow, and lymphoid organs of patients with chronic lymphocytic leukemia (CLL). In the tissue compartments, CLL shape a protective microenvironment by coopting normal elements. The efficacy of drugs that target these interactions further underscores their importance in the pathogenesis of CLL. While the B cell receptor (BCR) pathway clearly plays a central role in the CLL microenvironment, there is also rationale to evaluate agents that inhibit other aspects or modulate the immune cells in the microenvironment. Here we review the main cellular components, soluble factors, and signaling pathways of the CLL microenvironment, and highlight recent clinical advances. As the BCR pathway is reviewed elsewhere, we focus on other aspects of the microenvironment.