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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Adhesion Molecules / genetics
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / pathology
  • Lymphoma, B-Cell / therapy
  • Molecular Targeted Therapy*
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • Tumor Microenvironment / genetics*

Substances

  • Cell Adhesion Molecules