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Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia

Grimwade, D., Gorman, P., Duprez, E., Howe, K., Langabeer, S., Oliver, F., Walker, H., Culligan, D., Waters, J., Pomfret, M., Goldstone, A., Burnett, Alan Kenneth, Freemont, P., Sheer, D. and Solomon, E. 1997. Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. Blood 90 (12) , pp. 4876-4885.

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: American Society of Hematology
ISSN: 0006-4971
Last Modified: 25 Jun 2017 04:43
URI: http://orca.cf.ac.uk/id/eprint/59140

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