Breakage and fusion of the TEL (ETV6) gene in immature B lymphocytes induced by apoptogenic signals.
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.
Eguchi-Ishimae
M
M
Department of Virology, National Children's Medical Research Center, Tokyo, Japan. mieguchi@icr.ac.uk
Eguchi
M
M
Ishii
E
E
Miyazaki
S
S
Ueda
K
K
Kamada
N
N
Mizutani
S
S
D000628:Aminophylline / Q000494:pharmacology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D001483:Base Sequence; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D050676:Core Binding Factor Alpha 2 Subunit; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D020156:Salicylic Acid / Q000494:pharmacology; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D000097764:ETS Translocation Variant 6 Protein
D000628:Aminophylline; D050676:Core Binding Factor Alpha 2 Subunit; D016895:Culture Media, Serum-Free; D005047:Etoposide; D006861:Hydrogen Peroxide; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D020156:Salicylic Acid; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein