Hewamana S, Alghazal S, Lin TT, et al. Blood. 2008;111:4681-9.
The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target.
 

The NF-κB family of transcription factors has been implicated in diverse cellular processes, including cell proliferation, differentiation, survival, and inflammatory responses, among numerous others. At least three NF-κB cascades have been characterized: the classical or canonical pathway, which is induced by cytokines such as TNFα; the non-classical, or alternative pathway, which is triggered by BAFF and CD40 ligation; and the atypical pathway, which is engaged by DNA damage. Activation of NF-κB leads to transcription of numerous genes, many of which (for example, XIAP and Bcl-xL) serve survival functions. Not unexpectedly, NF-κB activation occurs in many tumor types, particularly hematologic malignancies. For example, multiple myeloma cells have long been thought to depend heavily upon NF-κB activation for their survival, and several recent studies have documented a high incidence of abnormalities involving genes associated with NF-κB activation in patient-derived myeloma cells. In addition, NF-κB activation is characteristic of AML cells in general, as well as in AML stem cells. A corollary of these observations is that NF-κB represents a logical candidate for therapeutic intervention.

CLL is an accumulative disease of mature, differentiated lymphocytes. Although activation of the classical and alternative pathways has been implicated in CLL cell survival, the clinical relevance of these observations has not been clearly defined. However, a recent study by Hewamana, et al. may shed significant light on this issue. In this study, the authors examined NF-κB DNA binding, reflected by EMSA assays, in cells from a series of patients with CLL and sought correlations with more established prognostic indicators. They also tested whether the extent of NF-κB activation predicted resistance of cells to conventional and novel agents. While the authors observed considerable inter-sample variability in basal NF-κB activation status, clear correlations were observed between activation and certain known negative prognostic indicators (e.g., high white count, short doubling time), although not between others (e.g., ZAP-70 expression). Interestingly, cells exhibiting high basal NF-κB activity were less sensitive to the established agent fludarabine, but more sensitive to the novel agent, LC-1, a parthenolide analog that inhibits IKK and has recently been shown to be active against AML stem cells.

One implication of this study is that, as recently suggested in the case of other hematologic malignancies such as multiple myeloma and AML, the NF-κB pathway may not only be an important prognostic determinant in CLL, but could also represent a logical target for pharmacologic intervention in this disorder. In this context, the results of a recent preclinical study suggested that synergistic interactions between the proteasome inhibitor bortezomib and histone deacetylase inhibitors in primary CLL cells involved, at least in part, NF-κB inactivation.1  The broader implication of the present study is that, as more sophisticated gene and protein profiling classification systems are developed in CLL and other hematologic malignancies, their ultimate benefit may lie in guiding the development of more rational, mechanism-based, targeted forms of therapy.

1.
Dai Y, Chen S, Kramer LB, et al. Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res. 2008;14:549-58.

Competing Interests

Dr. Grant indicated no relevant conflicts of interest.