Targeting inflammatory pathways in chronic lymphocytic leukemia

Abstract

Despite recent major advances in leukemia research, the pathobiology of chronic lymphocytic leukemia (CLL) remains poorly understood. Herein we review the role chronic inflammation plays in the initiation and progression of CLL. The robust production of inflammatory cytokines and chemokines accompanied by activation of intra-cellular pro-inflammatory pathways, and the presence of somatic mutations that activate pro-inflammatory signaling pathways, suggest that chronic inflammation plays a pathophysiological role in this disease. Indeed, glucocorticoids and non-steroidal anti-inflammatory possess anti-tumor activity, and glucocorticoids have been broadly used to treat CLL and its complications. Recent clinical trials demonstrated that tyrosine kinase inhibitors, such as ibrutinib and the immune-modulatory agent lenalidomide, induced impressive clinical responses in CLL patients with relapsed or refractory disease. As those pro-inflammatory pathway inhibitors and immune modulating drugs proved to be effective in CLL, other agents with similar activities are currently investigated in clinical trials. New insights into the pathobiology of CLL and the development of novel classes of drugs will undoubtedly provide us with effective tools to treat and perhaps cure CLL.

Keywords: CLL; Chronic lymphocytic leukemia; Experimental therapy; Inflammation.

Figure 1

Serum cytokine and chemokine levels in patients with CLL and healthy individuals (Yan et al. (2011). Serum cytokine and chemokine levels were measured in 84 CLL patients and 49 age-matched healthy individuals. Shown are cytokine and chemokine levels that were high, compared to healthy controls, in patients with both IgHV-mutated and –unmutated CLL. Data are depicted according to cytokine levels in serum. A. Low levels: IL-5, IL-4, IL-10, IFN-γ, and IL-17. B. Medium levels: granulocyte macrophage colony-stimulating factor receptor (GM-CSF), IL-1β, IL-8, IL-6, Ifα, IL-2, IL-15, and CCL3. C. High levels: CXCL11, CCL17, CCL4, CXCL10, IL-12, CCL19, CCL11, CXCL9, and CCL2 [11].

Figure 2

Signaling pathways activated in CLL cells. Upon attachment to their corresponding receptors (A, B and C) various extracellular factors induce signal transduction and activate transcription of inflammatory cytokines and chemokines. A. Ligands binding to TLR induce MYD88-mediated activation of NF-κB via phosphorylation and ubiquitination of IκB, enabling nuclear localization and DNA binding of NF-κB. B. BCR activation recruits BTK, which in turn phosphorylates IκB and activates NF-κB. C. Several ligands phosphorylate membrane-bound tyrosine kinase and non-tyrosine kinase receptors or recruit JAKs that transduce signaling by activating STAT3, ERK, and/or AKT (not shown). Phosphorylated (p) STAT3 forms heterodimers, shuttles to the nucleus, and activates transcription. D. In CLL, STAT3 is constitutively phosphorylated. Because STAT3 activates STAT3, high levels of unphosphorylated STAT3 (USTAT3) are present in CLL cells. E. USTAT3 binds NF-κB in competition with IκB; USTAT3 that shuttles freely in and out of the nucleus “carries” into the nucleus NF-κB that binds to DNA and activates transcription. F. Both pSTAT3 and NF-κB induce production of inflammatory cytokines that provide CLL cells with survival advantage.

Figure 3

Chronic inflammation is induced in cells with wild-type or deleted ATM at different stages of the disease: At an early stage, wild-type ATM promotes TP53 DNA-damage repair and induction of chronic inflammation and production of inflammatory cytokines such as IL-6. When ATM is mutated, in the absence or presence of 11q deletion, less TP53 is produced and accumulating damaged DNA induces an inflammatory response. This effect is more prominent when the disease burden is high or during disease progression.