DNA-Dependent Protein Kinase Activity Correlates With Clinical and In Vitro Sensitivity of Chronic Lymphocytic Leukemia Lymphocytes to Nitrogen Mustards

• DOI: 10.1182/blood.v92.7.2213
• Publication Date: 2019-10-14T08:55:55Z
• Authors: Catherine Muller; Garyfallia Christ...; Bernard Salles; Lawrence Panasci
• Keywords: Aged, 80 and over; Male; 0301 basic medicine; DNA Repair; DNA, Neoplasm; DNA-Activated Protein Kinase; Middle Aged; Leukemia, Lymphocytic, Chronic, B-Cell; 3. Good health; DNA-Binding Proteins; 03 medical and health sciences; Cross-Linking Reagents; Doxorubicin; Drug Resistance, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Humans; Chlorambucil; Female; Amino Acid Sequence; Antineoplastic Agents, Alkylating; Cyclophosphamide; Aged; DNA Damage

AbstractThe objective of this study is to investigate the role of DNA-dependent protein kinase (DNA-PK) in the chronic lymphocytic leukemia (CLL) lymphocyte response to nitrogen mustard therapy. DNA-PK is a nuclear serine/threonine kinase that functions in DNA double-strand break repair and in the joining process in recombination mechanisms. In a series of 34 patients with B-CLL, either untreated (n = 16) or resistant to chlorambucil (n = 18), the kinase activity of the complex, as determined by its capacity to phosphorylate a peptide substrate in vitro, is increased in the resistant samples as compared with the untreated ones (24.4 ± 2.6 arbitrary units [a.u.] [range, 12.7 to 55.8 a.u.] versus 8.1 ± 2.8 a.u. [range, 0.9 to 44.5 a.u.], respectively (P < .0001]), independent of other clinical and biological factors. Linear regression analysis shows an excellent correlation between the level of DNA-PK activity and the inherent in vitro sensitivity of CLL lymphocytes to chlorambucil (r = .875, P =.0001). The regulation of DNA-PK activity was associated with increased DNA-binding activity of its regulatory subunit, the Ku heterodimer, in resistant samples. These results suggest that this activity is a determinant in the cellular response to chlorambucil and participates in the development of nitrogen mustard–resistant disease. The increase in DNA-PK activity might contribute to the enhanced cross-link repair that we previously postulated to be a primary mechanism of resistance to nitrogen mustards in CLL.