NF-kappaB-dependent regulation of the diagnostic marker CD10 and role of BCL-2 activity in histone deacetylase inhibitor-induced apoptosis in human B-lymphoma cell lines
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Abstract
Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease
with multiple distinct molecular subtypes. Increased NF-κB activity and expression of the
microRNA miR-155 (product of the BIC gene) are associated with one subtype, called
the activated B-cell (ABC) subtype. It is shown here that induction of NF-κB activity
leads to increased miR-155 expression, the levels of miR-155 in a panel of B-lymphoma
cell lines correlate with increased NF-κB activity, and the NF-κB p50/p65 heterodimer
binds to a specific DNA site in the BIC promoter. Also described is a regulatory network
wherein NF-κB-dependent up-regulation of miR-155 leads to reduced PU.1 transcription
factor expression and consequently reduced PU.1-driven expression of B-lymphoma
marker CD10 in the human B-lymphoma cell line BJAB.
Genetic variation in DLBCL can be used to explain the response of individual
patients to chemotherapy. One cancer therapeutic approach currently in clinical trials uses
histone deacetylase inhibitors (HDACi's) as a monotherapy or in combination with other
vi
agents. It is shown here that two pan-HDACi's, trichostatin A and vorinostat, induce
apoptosis in seven of eight human DLBCL cell lines. Ectopic over-expression of antiapoptotic
proteins BCL-2 and BCL-XL or the pro-apoptotic protein BIM in select
DLBCL cell lines can confer further resistance or sensitivity, respectively, to HDACi
treatment. Additionally, the BCL-2 family antagonist ABT-737 can increase the
sensitivity of several DLBCL cell lines to vorinostat-induced apoptosis, including the
HDACi-resistant SUDHL6 cell line. Moreover, one vorinostat-resistant variant of the
HDACi-sensitive cell line SUDHL4 has increased expression of anti-apoptotic proteins
BCL-XL and MCL-1 and decreased sensitivity to ABT-737, and a second such variant
cell line has increased expression of anti-apoptotic protein MCL-1. These results suggest
that the balance of anti- to pro-apoptotic BCL-2 family protein expression is important in
determining the sensitivity of DLBCL cell lines to HDACi-induced apoptosis. Thus, the
sensitivity of DLBCL cell lines to treatment with HDACi's appears to depend on the
complex regulation of BCL-2 family members, suggesting that the response of a subset of
DLBCL patients to HDACi treatment may benefit from co-treatment with BCL-2
antagonists.