title: Molecular analysis of simple variant translocations in acute promyelocytic leukemia.
abstract: The primary cytogenetic abnormality in acute promyelocytic leukemia (APL; FAB M3) is a reciprocal translocation, t(15;17)(q22;q12), which serves to fuse the PML gene on chromosome 15 to the retinoic acid receptor alpha (RARA) gene on chromosome 17. A PML-RARA fusion message transcribed from the der(15) is thought to mediate leukemogenesis. Two APL patients with simple variants of this translocation, t(3;15)(q21;q22) and t(X;15)(p11;q22), have previously been reported who lack cytogenetic involvement of chromosome 17, although their breakpoint positions on chromosome 15 still suggest the involvement of the PML gene. Here we report on a combined analysis by molecular genetics and in situ hybridization of these two patients, in which we wanted to determine whether the PML gene has alternative fusion partners or whether cryptic rearrangement of the RARA locus has occurred instead. A cryptic involvement of RARA was demonstrated in both patients by a combination of Southern analysis, reverse transcription coupled to PCR (RT-PCR), and fluorescence in situ hybridization. The results indicate an absolute requirement for the rearrangement of the RARA gene in the pathogenesis of APL and underline the importance of RARA during normal myeloid differentiation.
authors.affiliation: Somatic Cell Genetics Laboratory, Imperial Cancer Research Fund, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Borrow
authors.forename: J
authors.initials: J
authors.lastname: Shipley
authors.forename: K
authors.initials: K
authors.lastname: Howe
authors.forename: F
authors.initials: F
authors.lastname: Kiely
authors.forename: A
authors.initials: A
authors.lastname: Goddard
authors.forename: D
authors.initials: D
authors.lastname: Sheer
authors.forename: A
authors.initials: A
authors.lastname: Srivastava
authors.forename: A C
authors.initials: AC
authors.lastname: Antony
authors.forename: T
authors.initials: T
authors.lastname: Fioretos
authors.forename: F
authors.initials: F
authors.lastname: Mitelman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000648:ultrastructure; D002880:Chromosomes, Human, Pair 11 / Q000648:ultrastructure; D002884:Chromosomes, Human, Pair 15 / Q000648:ultrastructure*; D002886:Chromosomes, Human, Pair 17 / Q000648:ultrastructure*; D002893:Chromosomes, Human, Pair 3 / Q000648:ultrastructure; D002898:Chromosomes, Human, Pair 8 / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins; D014960:X Chromosome / Q000648:ultrastructure
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human