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 ORCID: https://orcid.org/0000-0002-9280-5281, Jenkins, Christopher, Guzman, Monica L., Jordan, Craig T., Neelakantan, Sundar, Crooks, Peter A., Burnett, Alan Kenneth, Pratt, Guy, Fegan, Christopher Daniel ORCID: https://orcid.org/0000-0001-9685-0621, Rowntree, Clare, Brennan, Paul ORCID: https://orcid.org/0000-0001-8792-0499 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:	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:	27 Jul 2023 01:07
URI:	https://orca.cardiff.ac.uk/id/eprint/28015

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