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Blood, 1 February 2001, Vol. 97, No. 3, pp. 737-743
NEOPLASIA
Breakage and fusion of the TEL (ETV6) gene in immature
B lymphocytes induced by apoptogenic signals
Minenori Eguchi-Ishimae,
Mariko Eguchi,
Eiichi Ishii,
Sumio Miyazaki,
Kazuhiro Ueda,
Nanao Kamada, and
Shuki Mizutani
From the Department of Virology, National Children's
Medical Research Center, Tokyo; Department of Cancer Cytogenetics,
Research Institute for Radiation Biology and Medicine, Hiroshima
University, Hiroshima; Division of Pediatrics, Hamanomachi Hospital,
Fukuoka; Department of Pediatrics, Saga University School of Medicine,
Saga; and Department of Pediatrics, Hiroshima University School of
Medicine, Hiroshima, Japan.
TEL-AML1 fusion resulting from the t(12;21)(p13;q22) is
one of the most common genetic abnormalities in childhood acute
lymphoblastic leukemia. Recent findings that site-specific cleavage of
the MLL gene can be induced by chemotherapeutic agents such
as topoisomerase-II inhibitors suggest that apoptogenic agents can
cause chromosomal translocations in hematopoietic cells. This study
demonstrates a possible relationship between exposure to apoptogenic
stimuli, TEL breaks, and the formation of
TEL-AML1 fusion in immature B lymphocytes. Short-term
culture of immature B cell lines in the presence of apoptogenic stimuli
such as serum starvation, etoposide, or salicylic acid induced
double-strand breaks (DSBs) in intron 5 of the TEL gene and
intron 1 of the AML1 gene. TEL-AML1
fusion transcripts were also identified by reverse
transcriptase-polymerase chain reaction (RT-PCR) analysis in cell
lines treated by serum starvation or aminophylline. DSBs within the
TEL gene were also associated with fusion to other unknown
genes, presumably as a result of chromosomal translocation. We also
examined 67 cord blood and 147 normal peripheral blood samples for the
existence of in-frame TEL-AML1 fusion
transcripts. One cord blood sample (1.5%) and 13 normal peripheral
blood samples (8.8%) were positive as detected by nested RT-PCR. These
data suggest that breakage and fusion of TEL and
AML1 may be relatively common events and that sublethal
apoptotic signals could play a role in initiating leukemogenesis via the promotion of DNA damage.
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