Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia.
Acute promyelocytic leukaemia (APL) is uniquely associated with chromosomal translocations that disrupt the gene encoding the retinoic acid receptor, RARA. In more than 99% of cases, this disruption results in the formation of a PML-RARA gene fusion. Two rare variants of APL have been described, in which RARA is fused to one of two other genes, PLZF and NPM. Although RARA dysregulation is evidently important in APL, the role of the various fusion partners remains unclear. We have characterized a fourth APL gene fusion, which links exons encoding the retinoic acid and DNA-binding domains of RARA to 5' exons of NuMA, a gene that encodes the nuclear mitotic apparatus protein. The NuMA-RARA fusion protein exists in sheet-like nuclear aggregates with which normal NuMA partly co-localizes. In contrast to t(15;17) APL, the intracellular distribution of PML is normal in these cells. Our results suggest that interference with retinoid signalling, and not disruption of PML organization, is essential to the APL phenotype and implicates for the first time an element of the mitotic apparatus in the molecular pathogenesis of human malignancy.
Wells
R A
RA
Department of Hematology, Toronto Hospital, University of Toronto, Ontario, Canada.
Catzavelos
C
C
Kamel-Reid
S
S
D000595:Amino Acid Sequence; D034961:Antigens, Nuclear; D001483:Base Sequence; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D002880:Chromosomes, Human, Pair 11; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D017931:DNA Primers; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry; D000072482:Retinoic Acid Receptor alpha; D008941:Spindle Apparatus; D014178:Translocation, Genetic
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D017931:DNA Primers; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha