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Semin Cancer Biol. 2014 Feb;24:71-81. doi: 10.1016/j.semcancer.2013.08.011. Epub 2013 Sep 7.

The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies.

Author information

1
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jaburger@mdanderson.org.
2
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. Electronic address: j.gribben@qmul.ac.uk.

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.

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

PMID:
24018164
DOI:
10.1016/j.semcancer.2013.08.011
[Indexed for MEDLINE]

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