title: Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia.
abstract: Acute promyelocytic leukemia (APL) is typified by the reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of PML-RARalpha and RARalpha-PML fusion genes. We have characterized 7 cases of morphologic APL found to lack the t(15; 17) on conventional cytogenetic assessment. In 6 of 7 cases, cryptic PML-RARalpha rearrangements were identified by reverse transcriptase-polymerase chain reaction and fluorescent in situ hybridization (FISH); whereas, in the remaining patient, APL was associated with the variant translocation, t(11; 17)(q23; q12-21), leading to the formation of PLZF-RARalpha and RARalpha-PLZF fusion genes. In each of the cases with cryptic PML-RARalpha rearrangements, PML-RARalpha transcripts were detected in the absence of RARalpha-PML, consistent with the concept that PML-RARalpha is the critical oncogenic fusion protein. In 4 of these cases with evaluable metaphase spreads, the occurrence of a nonreciprocal translocation was confirmed by FISH with sole formation of the PML-RARalpha fusion gene; in 3 cases with morphologically normal chromosomes 15 and 17, RARalpha was inserted into PML on 15q, whereas in the remaining patient the PML-RARalpha fusion arose due to insertion of 15q-derived material including PML into RARalpha on 17q. Immunofluorescence studies were performed using antibodies raised against PML and PIC 1, a ubiquitin-homology domain protein previously identified as an interaction partner of PML. In acute myeloid leukemia (AML) of subtypes other than M3, PIC 1 was localized to the nuclear membrane and colocalized with PML within discrete nuclear bodies. In APL cases with cryptic PML-RARalpha rearrangements, the characteristic microparticulate pattern of PML staining was detected with partial colocalization with PIC 1, indicative of disruption of the nuclear bodies; whereas in t(11; 17)-associated APL, PML and PIC 1 remained colocalized within discrete nuclear bodies, as observed in non-APL cases. Although deregulation of the putative growth suppressor PML and delocalization of other nuclear body constituents have been advocated to play a key role in the development of t(15; 17)-associated APL, the present study shows that disruption of PML nuclear bodies per se is not a prerequisite for the pathogenesis of APL.
authors.affiliation: Cancer Genetics Laboratory, Division of Medical & Molecular Genetics, UMDS, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Grimwade
authors.forename: P
authors.initials: P
authors.lastname: Gorman
authors.forename: E
authors.initials: E
authors.lastname: Duprez
authors.forename: K
authors.initials: K
authors.lastname: Howe
authors.forename: S
authors.initials: S
authors.lastname: Langabeer
authors.forename: F
authors.initials: F
authors.lastname: Oliver
authors.forename: H
authors.initials: H
authors.lastname: Walker
authors.forename: D
authors.initials: D
authors.lastname: Culligan
authors.forename: J
authors.initials: J
authors.lastname: Waters
authors.forename: M
authors.initials: M
authors.lastname: Pomfret
authors.forename: A
authors.initials: A
authors.lastname: Goldstone
authors.forename: A
authors.initials: A
authors.lastname: Burnett
authors.forename: P
authors.initials: P
authors.lastname: Freemont
authors.forename: D
authors.initials: D
authors.lastname: Sheer
authors.forename: E
authors.initials: E
authors.lastname: Solomon
mesh_terms: D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D005455:Fluorescent Antibody Technique; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein