The NF-B subunit, Rel A, is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukaemia and represents a promising therapeutic target.

Saman Hewamana, Suhair Alghazal, Thet Thet Lin, Matthew Clement, Chris Jenkins, Monica L. Guzman, Craig T Jordan, Sundar Neelakantan, Peter A Crooks, Alan K Burnett, Guy Pratt, Chris Fegan, Clare Rowntree, Paul Brennan, Chris Pepper

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

In this study, we characterized nuclear factor κB (NF-κB) subunit DNA binding in chronic lymphocytic leukemia (CLL) samples and demonstrated heterogeneity in basal and inducible NF-κB. However, all cases showed higher basal NF-κB 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-κB 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 LD50 of 2.8 μM 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-κB DNA binding and sensitivity to LC-1 correlated with basal Rel A DNA binding (P = .03, r2 = 0.15). Furthermore, Rel A DNA binding was inversely correlated with sensitivity to fludarabine (P = .001, r2 = 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.
Original languageEnglish
Pages (from-to)4681-4689
Number of pages9
JournalBlood
Volume111
Issue number9
Early online date28 Jan 2008
DOIs
Publication statusPublished - 1 May 2008
Externally publishedYes

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