By Steven Grant, MD
2008-07-01
Dr. Grant indicated no relevant conflicts of interest.
Hewamana S, Alghazal S, Lin TT, et al. 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. Blood. 2008;111:4681-9.
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.
References
- 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.
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