title: The biological significance of the multidrug resistance gene MRP in inversion 16 leukemias.
abstract: Multidrug resistance represents an important mechanism by which leukaemic and solid tumour cells escape cell death after exposure to anthracyclines and other natural products. Acute myeloid leukaemia (AML) associated with the inversion chromosome 16: inv(16)(p13q22) has a favourable prognosis and is known to be chemosensitive. The inversion chromosome is seen in a number of FAB subclasses but is most commonly associated with acute myelomonocytic leukaemia with abnormal eosinophils, M4Eo. It results in the creation of a fusion between the myosin heavy chain gene (MYH11) on the short arm and the gene for a transcription factor, core binding factor beta (CBFB) on the long arm. In a subset of these inv(16) AML patients, inversion also results in loss of the gene for the multidrug resistance protein (MRP) at the short arm breakpoint. This gene maps to 16p13.13, centromeric to the primary short arm breakpoint, separated from MYH11 by a distance of approximately 150kb. Deletion of the MRP gene has been demonstrated by in situ hybridisation, gene dosage studies and by loss of heterozygosity of a flanking microsatellite marker (D16S405). Twenty two patients with inv(16) leukaemia were analysed for deletion of the MRP gene. Deletion of the gene was detected in seven patients, fourteen patients showed retention of the gene and in one case the findings were indeterminate. Clinical data from 13 of these patients were analysed revealing deletion of the MRP gene to be significantly associated with longer time from diagnosis until failure (death or relapse from complete remission) in these patients (p = 0.007). From this work and the growing literature concerning MRP, it appears likely that the deletion of an MRP allele, may favourably affect the biology of inv(16) AML and may have important prognostic implications.
authors.affiliation: Centre for Medical Genetics, Dept of Cytogentics & Molecular Genetics, Womens & Childrens Hospital, North Adelaide, South Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Kuss
authors.forename: R G
authors.initials: RG
authors.lastname: Deeley
authors.forename: S P
authors.initials: SP
authors.lastname: Cole
authors.forename: C L
authors.initials: CL
authors.lastname: Willman
authors.forename: K J
authors.initials: KJ
authors.lastname: Kopecky
authors.forename: S R
authors.initials: SR
authors.lastname: Wolman
authors.forename: H J
authors.initials: HJ
authors.lastname: Eyre
authors.forename: D F
authors.initials: DF
authors.lastname: Callen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D007446:Chromosome Inversion; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics / Q000648:ultrastructure*; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004804:Eosinophils / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C095514:CBFbeta-MYH11 fusion protein