1. Functional analysis of the ATM-p53-p21 pathway in the LRF CLL4 trial: blockade at the level of p21 is associated with short response duration.
- Author
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Lin K, Adamson J, Johnson GG, Carter A, Oates M, Wade R, Richards S, Gonzalez D, Matutes E, Dearden C, Oscier DG, Catovsky D, and Pettitt AR
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins genetics, Chlorambucil administration & dosage, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclophosphamide administration & dosage, DNA-Binding Proteins genetics, Female, Flow Cytometry, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Male, Middle Aged, Mutation, Prognosis, Protein Serine-Threonine Kinases genetics, Randomized Controlled Trials as Topic, Signal Transduction drug effects, Signal Transduction genetics, Survival Analysis, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins genetics, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Cell Cycle Proteins metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, DNA-Binding Proteins metabolism, Protein Serine-Threonine Kinases metabolism, Signal Transduction physiology, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Purpose: This study sought to establish whether functional analysis of the ATM-p53-p21 pathway adds to the information provided by currently available prognostic factors in patients with chronic lymphocytic leukemia (CLL) requiring frontline chemotherapy., Experimental Design: Cryopreserved blood mononuclear cells from 278 patients entering the LRF CLL4 trial comparing chlorambucil, fludarabine, and fludarabine plus cyclophosphamide were analyzed for ATM-p53-p21 pathway defects using an ex vivo functional assay that uses ionizing radiation to activate ATM and flow cytometry to measure upregulation of p53 and p21 proteins. Clinical endpoints were compared between groups of patients defined by their pathway status., Results: ATM-p53-p21 pathway defects of four different types (A, B, C, and D) were identified in 194 of 278 (70%) samples. The type A defect (high constitutive p53 expression combined with impaired p21 upregulation) and the type C defect (impaired p21 upregulation despite an intact p53 response) were each associated with short progression-free survival. The type A defect was associated with chemoresistance, whereas the type C defect was associated with early relapse. As expected, the type A defect was strongly associated with TP53 deletion/mutation. In contrast, the type C defect was not associated with any of the other prognostic factors examined, including TP53/ATM deletion, TP53 mutation, and IGHV mutational status. Detection of the type C defect added to the prognostic information provided by TP53/ATM deletion, TP53 mutation, and IGHV status., Conclusion: Our findings implicate blockade of the ATM-p53-p21 pathway at the level of p21 as a hitherto unrecognized determinant of early disease recurrence following successful cytoreduction.
- Published
- 2012
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