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Characterization of Cryptic Rearrangements and Variant Translocations in Acute Promyelocytic Leukemia
David Grimwade,
Patricia Gorman,
Estelle Duprez,
Kathy Howe,
Stephen Langabeer,
Fiona Oliver,
Helen Walker,
Dominic Culligan,
Jonathan Waters,
Mark Pomfret,
Anthony Goldstone,
Alan Burnett,
Paul Freemont,
Denise Sheer, and
Ellen Solomon
From the Cancer Genetics Laboratory, Division of Medical & Molecular Genetics, UMDS, London, UK; the Human Cytogenetics and Protein Structure Laboratories, Imperial Cancer Research Fund, London, UK; the Department of Haematology, UCL Hospitals, London, UK; the Department of Haematology, Aberdeen Royal Hospitals NHS trust, Aberdeen, UK; and the Department of Haematology, University of Wales, Cardiff, UK; and the Regional Genetic Services, Cytogenetics Laboratory, Birmingham Heartlands Hospital, Birmingham, UK.
Acute promyelocytic leukemia (APL) is typified by the reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of PML-RAR and RAR-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-RAR 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-RAR and RAR-PLZF fusion genes. In each of the cases with cryptic PML-RAR rearrangements, PML-RAR transcripts were detected in the absence of RAR-PML, consistent with the concept that PML-RAR 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-RAR fusion gene; in 3 cases with morphologically normal chromosomes 15 and 17, RAR was inserted into PML on 15q, whereas in the remaining patient the PML-RAR fusion arose due to insertion of 15q-derived material including PML into RAR 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-RAR 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.
Blood, Vol. 90 No. 12 (December 15), 1997:
pp. 4876-4885
© 1997 by The American Society of Hematology.
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