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Etoposide causes illegitimate V(D)J recombination in human lymphoid
leukemic cells
CL Chen, JC Fuscoe, Q Liu and MV Relling
Department of Pharmaceutical Sciences, St Jude Children's Research
Hospital, Memphis, TN 38101-0318, USA.
Etoposide is one of the most widely used antineoplastics. Unfortunately,
the same treatment schedules associated with impressive efficacy are
associated with an increased risk of secondary acute myeloid leukemia
(AML), which has prompted its withdrawal from some treatment regimens,
thereby potentially compromising efficacy against the original tumor.
Because etoposide-associated AML is characterized by site-specific
illegitimate DNA recombination, we studied whether etoposide could directly
cause site-specific deletions of exons 2 and 3 in the hprt gene. Human
lymphoid CCRF-CEM cells were treated with etoposide for 4 hours, and DNA
was isolated after subculturing. The deletion of exons 2 and 3 from hprt
was assayed by a quantitative polymerase chain reaction (PCR) method. In
the absence of etoposide treatment, the frequency of deletions of exons 2
and 3 was very low (5.05 x 10(-8)). After exposure to 10 mumol/ L
etoposide, the frequency of the exon 2 + 3 deletion was increased
immediately after and at 24 hours after etoposide treatment (65 to 89 x
10(-8)) and increased to higher levels (128 to 173 x 10(-8)) after 2 and 6
days of subculture (P < .001 overall). The frequency of the exon 2 + 3
deletion assessed at 6 days of subculture after 4 hours of 0, 0.25, 1, 2.5,
5, and 10 mumol/L etoposide treatment increased with etoposide
concentration, ie, 5.05 x 10(-8), 89.2 x 10(-8), 108 x 10(-8), 142 x
10(-8), 163 x 10(-8), and 173 x 10(-8), respectively (P < .0001).
Sequencing of a subset of amplified products confirmed the presence of DNA
sequences at the breakpoints consistent with V(D)J recombination. By
contrast, exon 2 + 3 deletions after etoposide treatment in the myeloid
cell lines KG-1A and K562 showed no evidence of V(D)J recombinase in their
genesis. We conclude that etoposide can induce the illegitimate
site-specific action of V(D)J recombinase on an unnatural DNA substrate
after a single treatment in human lymphoid cells.
Volume 88,
Issue 6,
pp. 2210-2218,
09/15/1996
Copyright © 1996 by The American Society of Hematology
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