title: 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.
abstract: 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.
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Saman
authors.initials: S
authors.lastname: Hewamana
authors.forename: Suhair
authors.initials: S
authors.lastname: Alghazal
authors.forename: Thet Thet
authors.initials: TT
authors.lastname: Lin
authors.forename: Matthew
authors.initials: M
authors.lastname: Clement
authors.forename: Chris
authors.initials: C
authors.lastname: Jenkins
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.forename: Sundar
authors.initials: S
authors.lastname: Neelakantan
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.forename: Clare
authors.initials: C
authors.lastname: Rowntree
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
mesh_terms: 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
chemical_list: D051996:Transcription Factor RelA; D004247:DNA