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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

Hewamana, Saman, Alghazal, Suhair Alkailani, Lin, Thet Thet, Clement, Matthew, Jenkins, Christopher, Guzman, Monica L., Jordan, Craig T., Neelakantan, Sundar, Crooks, Peter A., Burnett, Alan Kenneth, Pratt, Guy, Fegan, Christopher Daniel, Rowntree, Clare, Brennan, Paul and Pepper, Christopher John 2008. 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 111 (9) , pp. 4681-4689. 10.1182/blood-2007-11-125278

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Society of Hematology
ISSN: 0006-4971
Last Modified: 09 Jan 2018 19:57
URI: http://orca-mwe.cf.ac.uk/id/eprint/28015

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