Molecular Pathways: Targeting the Microenvironment in Chronic Lymphocytic Leukemia—Focus on the B-Cell Receptor

Abstract

Interactions between malignant B lymphocytes and the tissue microenvironment play a major role in the pathogenesis of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. The coexistence and coevolution of CLL cells with their tissue neighbors provided the basis for discovery of critical cellular and molecular drivers of the disease and identification of new therapeutic targets. Bone marrow stromal cells (BMSC), monocyte-derived nurselike cells (NLC), and T cells are key players in the CLL microenvironment, which activate and protect CLL cells within the tissues. CLL surface molecules, such as the B-cell antigen receptor (BCR), chemokine receptors, adhesion molecules, and TNF receptor superfamily members (e.g., CD40, BCMA, and BAFF-R) engage in cross-talk with respective tissue ligands. This cross-talk results in survival and expansion of the CLL clone, and protects CLL cells from conventional cytotoxic drugs. Inhibiting these pathways represents an alternative therapeutic strategy to more conventional chemoimmunotherapy. Here, we review central components of the CLL microenvironment, with a particular emphasis on BCR signaling, and we summarize the most relevant clinical advances with inhibitors that target the BCR-associated spleen tyrosine kinase/SYK (fostamatinib), Bruton's tyrosine kinase/BTK (ibrutinib), and PI3Kd (idelalisib). Clin Cancer Res; 20(3); 548-56. Ó2013 AACR.

Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC subversion induces up-regulation of PKC II expression in B lymphocytes

“…51 Therefore, inhibition of PKCb may modify the tumor microenvironment, which has been established to play a critical role in supporting CLL survival, proliferation and chemoresistance. 52 Collectively, our results demonstrate the potential for therapeutic agents targeting PI3K/PKCb−related signaling pathways, and highlight the translational applicability of the PKCa-KR mouse model as a pre-clinical model for the development of poor prognostic CLL. Moreover, our mouse model provides a powerful tool for delineating the molecular events that occur downstream of PKCa subversion during the initiation of cellular transformation, enabling the identification of potential novel therapeutic targets for CLL.…”

Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma

“…Enhanced PI3K signaling is associated with oncogenesis (8), and constitutive activation of the PI3K pathway has been observed in multiple hematologic malignancies, including lymphoma and CLL (4,7,(9)(10)(11). In CLL, activation of the PI3K pathway is a consequence of activation of the BCR, integrin, and chemokine receptors (4,9,11,12). Activation of the PI3K pathway is associated with poor outcome in patients with diffuse large Bcell lymphoma (DLBCL; refs.…”

Therapeutic targeting of microenvironment in follicular lymphoma

“…It has been recognized that the inhibitors of the BCR pathway have an impact on both the immune and the nonimmune microenvironment. 28 Although the contribution of microenvironmental effects to overall antitumor activity of these agents is difficult to assess, understanding their impact on microenvironment function is critical to the rational development of therapies combining these agents with other agents targeting the microenvironment.…”