Microenvironment dependency in Chronic Lymphocytic Leukemia: The basis for new targeted therapies

Chronic Lymphocytic Leukemia (CLL) is a prototype microenvironment-dependent B-cell malignancy, in which the neoplastic B cells co-evolve together with a supportive tissue microenvironment, which promotes leukemia cell survival, growth, and drug-resistance. Chemo-immunotherapy is an established treatment modality for CLL patients, resulting in high rates of responses and improved survival, especially in low-risk CLL. New, alternative treatments target B-cell receptor (BCR) signaling and the Chemokine (C–X–C motif) Receptor 4 (CXCR4)–Chemokine (C–X–C motif) Ligand 12 (CXCL12) axis, which are key pathways of CLL-microenvironment cross talk. The remarkable clinical efficacy of inhibitors targeting the BCR-associated kinases Bruton's tyrosine kinase (BTK) and phosphoinositide 3-kinase delta (PI3Kδ) challenges established therapeutic paradigms and corroborates the central role of BCR signaling in CLL pathogenesis. In this review, we discuss the cellular and molecular components of the CLL microenvironment. We also describe the emerging therapeutic options for CLL patients, with a focus on inhibitors of CXCR4–CXCL12 and BCR signaling.