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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2213-2219
DNA-Dependent Protein Kinase Activity Correlates With Clinical and In
Vitro Sensitivity of Chronic Lymphocytic Leukemia Lymphocytes to
Nitrogen Mustards
Catherine Muller,
Garyfallia Christodoulopoulos,
Bernard Salles, and
Lawrence Panasci
From the Institut de Pharmacologie et de Biologie Structurale (CNRS
UPR 9062), Toulouse, France; and the Lady Davis Institute for Medical
Research, The Sir Mortimer B. Davis-Jewish General Hospital, Montreal,
Quebec, Canada.
The 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.
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