Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.
A unique mRNA produced in leukemic cells from a t(15;17) acute promyelocytic leukemia (APL) patient encodes a fusion protein between the retinoic acid receptor alpha (RAR alpha) and a myeloid gene product called PML. PML contains a cysteine-rich region present in a new family of apparent DNA-binding proteins that includes a regulator of the interleukin-2 receptor gene (Rpt-1) and the recombination-activating gene product (RAG-1). Accordingly, PML may represent a novel transcription factor or recombinase. The aberrant PML-RAR fusion product, while typically retinoic acid responsive, displays both cell type- and promoter-specific differences from the wild-type RAR alpha. Because patients with APL can be induced into remission with high dose RA therapy, we propose that the nonliganded PML-RAR protein is a new class of dominant negative oncogene product. Treatment with RA would not only relieve this inhibition, but the activated PML-RAR protein may actually promote myelocyte differentiation.
Kakizuka
A
A
Salk Institute for Biological Studies, La Jolla, California 92037.
Miller
W H
WH
Umesono
K
K
Warrell
R P
RP
Frankel
S R
SR
Murty
V V
VV
Dmitrovsky
E
E
Evans
R M
RM
D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009841:Oligonucleotides / Q000737:chemistry; D009857:Oncogenes; D016133:Polymerase Chain Reaction; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D014178:Translocation, Genetic; D014212:Tretinoin; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009841:Oligonucleotides; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin; D004247:DNA