Heterogenous fusion transcripts involving the NUP98 gene and HOXD13 gene activation in a case of acute myeloid leukemia with the t(2;11)(q31;p15) translocation.
We report the characterization of a rare chromosomal translocation, a t(2;11)(q31;p15), which occurred in a patient with de novo acute myeloid leukemia (AML-M4). By 3'-RACE and RT-PCR analyses, two kinds of NUP98-HOXD13 fusion transcript were detected. In addition, we identified a novel fusion transcript, NUP98-FN1, in the same patient. Ectopic expression of the wild-type HOXD13 gene was also observed in the patient, suggesting that HOXD13 contributes to the development of this type of leukemia. The NUP98-HOXD13 fusion transcript was predicted to encode a 552 or 569-amino acid protein containing the Phe-Gly (FG) repeat region of NUP98 and the homeodomain of HOXD13. The NUP98-FN1 fusion transcript was predicted to encode a 482 or 499-amino acid protein consisting of the same N-terminal region of NUP98 and a C-terminal region of 12 amino acids derived from a previously unidentified sequence. We isolated and characterized the chromosomal breakpoints. The breakpoint at 11p15 is mapped within a LINE repetitive element in a 9 kb intron of NUP98, and more than 60% of the sequenced 3 kb region surrounding the breakpoint junction consists of repetitive elements. The other breakpoint at 2q31 is in an intron of FN1, which is located 7 kb upstream of HOXD13, and the repetitive sequence content of the breakpoint junction is low. Local sequence duplications at genomic breakpoints suggest that the t(2;11) translocation is mediated through staggered double-strand DNA breaks. These results throw light on the mechanisms responsible for the generation of t(2;11) translocation and on the processes leading to t(2;11) leukemia.
Arai
Y
Y
Cancer Genomics Division, National Cancer Research Institute, Tokyo, Japan.
Kyo
T
T
Miwa
H
H
Arai
K
K
Kamada
N
N
Kita
K
K
Ohki
M
M
D000208:Acute Disease; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D019457:Chromosome Breakage; D002880:Chromosomes, Human, Pair 11; D002889:Chromosomes, Human, Pair 2; D003001:Cloning, Molecular; D004273:DNA, Neoplasm / Q000032:analysis; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins / Q000235:genetics*; D012313:RNA; D014157:Transcription Factors; D014178:Translocation, Genetic
D004273:DNA, Neoplasm; C513184:HOXD13 protein, human; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; C039919:RNA, recombinant; D014157:Transcription Factors; C093350:nuclear pore complex protein 98; D012313:RNA