title: Heterogenic molecular basis for loss of ABL1-BCR transcription: deletions in der(9)t(9;22) and variants of standard t(9;22) in BCR-ABL1-positive chronic myeloid leukemia.
abstract: The objective of this study was to characterize the ABL1-BCR fusion gene in 76 BCR-ABL1-positive chronic myeloid leukemia (CML) patients regarding expression as well as genomic status, to assess the frequency of ABL1-BCR gene deletion in these patients, which has been reported to be an adverse prognostic factor in Philadelphia chromosome-positive CML. Patients were analyzed for ABL1-BCR 1b-b3 and/or 1b-b4 transcription by RT-PCR analysis. ABL1-BCR gene status was analyzed by FISH in 16 CML patients with no ABL1-BCR transcript. FISH revealed a partial or total deletion of the ABL1-BCR gene in 9/16 and localized the 5' portion of ABL1 and the 3' portion of BCR at separated loci in 5/16 patients. The latter FISH pattern resulted from a nonreciprocal translocation in two and a complex translocation in three individuals. In 2/16 patients, FISH could not exclude an intact ABL1-BCR fusion gene. Thus, most CML patients without ABL1-BCR transcript could be characterized cytogenetically to belong to two major subgroups: a silent ABL1-BCR gene was attributed to a deletion in der(9)t(9;22) in 56% of the investigated patients or to variants of a standard t(9;22) (approximately 31%). Conversely, none of the 50 patients with an ABL1-BCR transcript exhibited a variant t(9;22) in GTG-banding analysis. Thus, genomic aberrations such as deletions or complex genomic rearrangements are the basic and most frequent cause for ABL1-BCR RNA negativity in CML. The heterogeneity of the underlying molecular mechanisms may explain divergent clinical implications described for patients with an ABL1-BCR deletion and those with no ABL1-BCR transcript.
authors.affiliation: Institute for Human Genetics and Anthropology, FSU, Jena, Germany. ilon@mti-n.uni-jena.de
authors.forename: Ivan F
authors.initials: IF
authors.lastname: Loncarevic
authors.forename: Jennifer
authors.initials: J
authors.lastname: Römer
authors.forename: Heike
authors.initials: H
authors.lastname: Starke
authors.forename: Anita
authors.initials: A
authors.lastname: Heller
authors.forename: Cordula
authors.initials: C
authors.lastname: Bleck
authors.forename: Monika
authors.initials: M
authors.lastname: Ziegler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fiedler
authors.forename: Thomas
authors.initials: T
authors.lastname: Liehr
authors.forename: Joachim H
authors.initials: JH
authors.lastname: Clement
authors.forename: Uwe
authors.initials: U
authors.lastname: Claussen
mesh_terms: D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015342:DNA Probes / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics*; D016313:Genes, abl / Q000235:genetics*; D018740:Genetic Heterogeneity; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008297:Male; D012313:RNA / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D015342:DNA Probes; D012313:RNA; D016044:Fusion Proteins, bcr-abl