Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment

Abstract

Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions.

The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein

“…It is thus possible that the rewiring process induced by the ibrutinib resistance mutations also enhances the sensitivity of PLC␥ 2 to extracellular ligands of these cell surface proteins, such as cleavage fragments of the third complement component, pathogen-derived molecules, extracellular matrix proteins, and chemokines. This may ultimately allow costimulatory signals to become stimulatory in their own right and as such to alter the interactions of the ibrutinib-resistant tumor cells with their protective microenvironments, for example (57). Interestingly, integrin-mediated adhesion and migration in response to the chemokines CXCL12 or CXCL13, as well as in vivo homing to lymphoid organs, was impaired in Btk-deficient (pre-)B cells, whereas CXCL12-mediated activation of Rac was intact.…”

Extracellular vesicles released from chronic lymphocytic leukemia cells exhibit a disease relevant mRNA signature and transfer mRNA to bystander cells

“…3 Recently the relevance of extracellular vesicles (EV) to the intercellular cross-talk and the establishment of a tumor-promoting CLL microenvironment was investigated in several studies. [4][5][6][7] EV are either shed from the cell surface or released as exosomes via exocytosis upon generation in multivesicular bodies.…”

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

“…3 It is within anatomic structures (the so-called proliferation centers) found in the LN that CLL cells encounter antigen together with costimulatory signals that drive proliferation and expansion. 4,5 Significant advances have been made in the therapy of CLL with the introduction of tyrosine kinase inhibitors. Bruton tyrosine kinase (Btk) and phosphatidylinositol 3-kinase inhibitors achieve long-lasting responses in the majority of patients, improving outcome with relatively limited toxicities.…”