title: Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia.
abstract: Many biologic markers are associated with poor prognosis in chronic lymphocytic leukemia (CLL), but their mechanistic role remains unclear. Bax is an essential proapoptotic protein and decreased levels in malignant cells lead to resistance to apoptosis. 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.
authors.affiliation: Centre for Haematology, Institute of Cell and Molecular Science, Departments of Haematology and Haemato-Oncology, Queen Mary University of London, UK. s.g.agrawal@qmul.ac.uk
authors.forename: Samir G
authors.initials: SG
authors.lastname: Agrawal
authors.forename: Feng-Ting
authors.initials: FT
authors.lastname: Liu
authors.forename: Catherine
authors.initials: C
authors.lastname: Wiseman
authors.forename: Sima
authors.initials: S
authors.lastname: Shirali
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Liu
authors.forename: Debra
authors.initials: D
authors.lastname: Lillington
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Du
authors.forename: Denise
authors.initials: D
authors.lastname: Syndercombe-Court
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Newland
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Li
authors.initials: L
authors.lastname: Jia
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D016019:Survival Analysis; D013816:Thermodynamics; D013997:Time Factors; D016896:Treatment Outcome; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D051028:bcl-2-Associated X Protein; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D046988:Proteasome Endopeptidase Complex