NF-kB and the CLL microenvironment

Abstract

Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia in the western world. Despite the positive clinical effects of new targeted therapies, CLL still remains an incurable and refractory disease and resistance to treatments are commonly encountered. The Nuclear Factor-Kappa B (NF-κB) transcription factor has been implicated in the pathology of CLL, with high levels of NF-κB associated with disease progression and drug resistance. This aberrant NF-κB activation can be caused by genetic mutations in the tumor cells and microenvironmental factors, which promote NF-κB signaling. Activation can be induced via two distinct pathways, the canonical and non-canonical pathway, which result in tumor cell proliferation, survival and drug resistance. Therefore, understanding how the CLL microenvironment drives NF-κB activation is important for deciphering how CLL cells evade treatment and may aid the development of novel targeting therapeutics. The CLL microenvironment is comprised of various cells, including nurse like cells, mesenchymal stromal cells, follicular dendritic cells and CD4+ T cells. By activating different receptors, including the B cell receptor and CD40, these cells cause overactivity of the canonical and non-canonical NF-κB pathways. Within this review, we will explore the different components of the CLL microenvironment that drive the NF-κB pathway, investigating how this knowledge is being translated in the development of new therapeutics.

Keywords: CLL; NF-kappaB signaling pathway; chronic lymphocytic leukemia; hematological malignancies; therapeutic targets; tumor microenvironment.

Figure 1

Schematic summary of the canonical and non-canonical NF-κB signaling pathways and the dimers formed by the 5 different subunits. The canonical signaling pathway is shown in green, and primarily induces RelA:p50 and cRel:p50 through the degradation of Inhibitors of NF-κB (IκBs). The non-canonical pathway is indicated in blue and primarily activates RelB:p52 through the processing of p100 into p52. The potential for bi-direction crosstalk between the two pathways is indicated in gray. Both p100 and RelB are target genes on canonical NF-κB signaling creating the potential for crosstalk from canonical to non-canonical signaling. P100 that is not processed into p52 can form an inhibitory complex that inhibits canonical dimers. This p100 can be degraded by NIK creating the potential for crosstalk from non-canonical signaling to canonical dimers. Additional crosstalk can occur due to the competition between p50 and p52 for binding to a limited pool of RelA and RelB.

Figure 2

Schematic summary of some of the components and interactions in the CLL microenvironment.