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.

Expression and Activity of the NF-κB Subunits in Chronic Lymphocytic Leukaemia: A Role for RelB and Non-Canonical Signalling

“…Moreover, in CLL cells stimulated to proliferate using CD40L-transfected cells, the rapid activation of RelB and p52 (which persisted throughout the co-culture period) confirms that CD40L-mediated stimulation of CLL cells is concomitant with non-canonical NF-κB pathway signalling. Previous studies have shown that canonical NF-κB signalling and non-canonical signalling occur following CD40L-stimulation [9]. Importantly, our observation that RelB and p52 activity was accompanied by phosphorylation of p100 (within 30 min of co-culture, Figure 5C) suggests that phosphorylation by IKKα, which is known to direct processing of p100 to the active p52, is a key event in this cascade.…”

“…As well as canonical NF-κB pathway signalling, the non-canonical NF-κB pathway is known to play a role in receptor signalling [9]. We used fibroblasts that stably express CD40L in a co-culture system to more closely model the in vivo microenvironment encountered by CLL cells in the lymphoid tissues.…”

“…The non-canonical NF-κB signalling pathway involves NF-κB-inducing kinase (NIK)induced activation of IKKα, which in turn promotes degradation of the p100 precursor into active p52 [6]. RelB and p52 are common heterodimeric partners and associated with a distinct set of stimuli, examples of which include the B-cell activating factor of the tumour necrosis factor family (BAFF) and the CD40 receptor [9]. Although the p52 (non-canonical) and p50 (canonical) subunits lack a transactivation domain, they cooperate with other Rel subunits or transcription factors (such as BCL3) at shared promoters, and different subunit dimer combinations may determine the specificity of the transcriptional response [5].…”

Prognostic Potential of Galectin-9 mRNA Expression in Chronic Lymphocytic Leukemia

“…Understanding the pathomechanisms associated with the clinical and therapeutic heterogeneity of CLL continues to be a challenge for modern personalized medicine. Within a decade, there have been many reports highlighting the role of the microenvironment in the pathogenesis of CLL [37][38][39][40][41]. Immune checkpoints are just one of many components that play an important role in the interactions between leukemic and surrounding cells [42].…”

NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia

“…The NF-κB family of transcription factors consists of homo- or heterodimers of the subunits p65, RelB, c-Rel, p50 and p52, which function as transcriptional activators or repressors of numerous genes that regulate cell proliferation, survival and differentiation [ 7 , 8 ]. These transcription factors are maintained inactive in the cytoplasm by the IκB inhibitor proteins, including the typical inhibitors IκBα, IκBβ, and IκBε, the atypical inhibitors IκBζ, BCL-3, IκB-NS, and IκBη, and the precursor proteins p100 and p105 [ 9 ].…”