title: The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies.
abstract: Over the last decade, the active role of the microenvironment in the pathogenesis of B cell lymphomas has been recognized, delivering signals that favor clonal expansion and drug resistance. We are only beginning to understand the complex cross talk between neoplastic B cells and the tissue microenvironment, for example in secondary lymphoid organs, but some key cellular and molecular players have emerged. Mesenchymal stromal cells, nurselike cells (NLC) and lymphoma-associated macrophages (LAM), in concert with T cells, natural killer cells and extracellular matrix components participate in the dialog with the neoplastic B cells. B cell receptor signaling, activation via TNF family members (i.e. BAFF, APRIL), and tissue homing chemokine receptors and adhesion molecules are important in the interaction between malignant B cells and their microenvironment. Disrupting this cross talk is an attractive novel strategy for treating patients with B cell malignancies. Here, we summarize the cellular and molecular interactions between B cell lymphoma/leukemia cells and their microenvironment, and the therapeutic targets that are emerging, focusing on small molecule inhibitors that are targeting B cell receptor-associated kinases SYK, BTK, and PI3Ks, as well as on immunomodulatory agents and T cell mediated therapies. Clinically relevant aspects of new targeted therapeutics will be discussed, along with an outlook into future therapeutic strategies.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jaburger@mdanderson.org.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. Electronic address: j.gribben@qmul.ac.uk.
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D058990:Molecular Targeted Therapy; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D015815:Cell Adhesion Molecules
keywords: B cell receptor; BCR; BTK; CLL; CXCL12; CXCR4; Chemokine receptors; Chemokines; Chronic lymphocytic leukemia; Microenvironment; NK cells; Nurselike cells; PI3Kδ; SYK; Stromal cells; T cells