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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4681-4689.
Prepublished online as a Blood First Edition Paper on January 28, 2008; DOI 10.1182/blood-2007-11-125278.
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NEOPLASIA
The NF- B subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target
Saman Hewamana1,2,
Suhair Alghazal1,
Thet Thet Lin1,
Matthew Clement2,
Chris Jenkins1,
Monica L. Guzman3,
Craig T. Jordan3,
Sundar Neelakantan4,
Peter A. Crooks4,
Alan K. Burnett1,
Guy Pratt5,
Chris Fegan1,
Clare Rowntree1,
Paul Brennan2, and
Chris Pepper1
Departments of1 Haematology and
2 Medical Biochemistry & Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom;
3 Division of Hematology/Oncology, University of Rochester School of Medicine, Rochester, NY;
4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington; and
5 Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom
In this study, we characterized nuclear factor  B (NF-B) subunit DNA binding in chronic lymphocytic leukemia (CLL) samples and demonstrated heterogeneity in basal and inducible NF-B. However, all cases showed higher basal NF-B 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-B 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-B 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.
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Related Article in Blood Online:
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CLL and activated NF-B: living partnership
- Erin Hertlein and John C. Byrd
Blood 2008 111: 4427.
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