The NF-kappaB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target.
In this study, we characterized nuclear factor kappaB (NF-kappaB) subunit DNA binding in chronic lymphocytic leukemia (CLL) samples and demonstrated heterogeneity in basal and inducible NF-kappaB. However, all cases showed higher basal NF-kappaB than normal B cells. Subunit analysis revealed DNA binding of p50, Rel A, and c-Rel in primary CLL cells, and Rel A DNA binding was associated with in vitro survival (P = .01) with high white cell count (P = .01) and shorter lymphocyte doubling time (P = .01). NF-kappaB induction after in vitro stimulation with anti-IgM was associated with increased in vitro survival (P < .001) and expression of the signaling molecule ZAP-70 (P = .003). Prompted by these data, we evaluated the novel parthenolide analog, LC-1, in 54 CLL patient samples. LC-1 induced apoptosis in all the samples tested with a mean LD(50) of 2.8 microM after 24 hours; normal B and T cells were significantly more resistant to its apoptotic effects (P < .001). Apoptosis was preceded by a marked loss of NF-kappaB DNA binding and sensitivity to LC-1 correlated with basal Rel A DNA binding (P = .03, r(2) = 0.15). Furthermore, Rel A DNA binding was inversely correlated with sensitivity to fludarabine (P = .001, r(2) = 0.3), implicating Rel A in fludarabine resistance. Taken together, these data indicate that Rel A represents an excellent therapeutic target for this incurable disease.
Hewamana
Saman
S
Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Alghazal
Suhair
S
Lin
Thet Thet
TT
Clement
Matthew
M
Jenkins
Chris
C
Guzman
Monica L
ML
Jordan
Craig T
CT
Neelakantan
Sundar
S
Crooks
Peter A
PA
Burnett
Alan K
AK
Pratt
Guy
G
Fegan
Chris
C
Rowntree
Clare
C
Brennan
Paul
P
Pepper
Chris
C
D017209:Apoptosis; D004247:DNA / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000032:analysis / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D051996:Transcription Factor RelA; D004247:DNA