Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia

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Abstract

Many biologic markers are associated with poor prognosis in chronic lymphocytic leukemia (CLL), but their mechanistic role remains unclear. Bax is an essential pro-apoptotic protein and decreased levels in malignant cells lead to resistance to apopto-sis. Using a Bax degradation activity (BDA) assay, CLL cells were found to show variable Bax instability. However, BDA did not correlate with Bax protein levels: BDA positive and negative cases had high and low baseline Bax levels. BDA positive cases showed a marked accumulation of poor prognostic markers-unmutated immunoglobulin heavy chain variable genes, ZAP-70/CD38 positivity, 11q22/17p13 deletion, and short lymphocyte doubling time. Patients with BDA positive cells had a shorter median overall survival (OS; 126 months vs not reached, P = .011) and time to first treatment (16 vs 156 months, P = .029) than BDA negative cases. Dual BDA and ZAP-70 positivity had a median OS of 84 months (P = .012). The BDA assay measures the intrinsic ubiquitin/proteasome activity of CLL cells and dynamic changes in Bax protein levels over time. Mechanistically, Bax instability may represent a final common pathway for disparate prognostic markers, as well as being itself an indicator of poor prognosis. © 2008 by The American Society of Hematology.

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Agrawal, S. G., Liu, F. T., Wiseman, C., Shirali, S., Liu, H., Lillington, D., … Jia, L. (2008). Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia. Blood, 111(5), 2790–2796. https://doi.org/10.1182/blood-2007-10-110460

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