Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product.
A chromosomal translocation, t(4;11)-(q21;q23), is associated with an aggressive mixed-lineage leukemia. A yeast artificial chromosome was used to clone the chromosomal breakpoint of this translocation in the RS4;11 cell line. The breakpoint sequences revealed an inverted repeat bordered by a consensus site for topoisomerase II binding and cleavage as well as chi-like elements. The der(11) chromosome encodes a fusion RNA and predicted chimeric protein between the 11q23 gene MLL and a 4q21 gene designated AF4. The sequence of the complete open reading frame for this fusion transcript reveals the MLL protein to have homology with DNA methyltransferase, the Drosophila trithorax gene product, and the "AT-hook" motif of high-mobility-group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant negative mechanism in leukemogenesis.
Domer
P H
PH
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110.
Fakharzadeh
S S
SS
Chen
C S
CS
Jockel
J
J
Johansen
L
L
Silverman
G A
GA
Kersey
J H
JH
Korsmeyer
S J
SJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002874:Chromosome Mapping; D015825:Chromosomes, Fungal; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D003001:Cloning, Molecular; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D011061:Poly A / Q000302:isolation & purification / Q000378:metabolism; D012313:RNA / Q000302:isolation & purification / Q000378:metabolism; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis*; D012091:Repetitive Sequences, Nucleic Acid; D015183:Restriction Mapping; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011061:Poly A; D012313:RNA; D004250:DNA Topoisomerases, Type II