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Interstitial insertion of retinoic acid receptor-alpha gene in acute
promyelocytic leukemia with normal chromosomes 15 and 17
LR Hiorns, T Min, GJ Swansbury, A Zelent, MJ Dyer and D Catovsky
Academic Department of Haematology and Cytogenetics, Royal Marsden
Hospital, Sutton, Surrey, UK.
The translocation t(15;17)(q22;q21) is seen exclusively in patients with
acute promyelocytic leukemia (APL) and in the promyelocytic blast crisis of
chronic myeloid leukemia (CML). This translocation juxta- poses the
promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid
receptor-alpha (RARA) gene on chromosome 17, resulting in the formation of
a chimeric mRNA transcript. We describe a patient with the microgranular
variant form of APL, with no detectable cytogenetic abnormality of either
chromosomes 15 or 17, who nevertheless had juxtaposition of PML and RARA
genes and expressed a chimeric transcript. Conventional cytogenetics showed
the karyotype 46,XY,d- er(3)t(3;8)(p25;q12). Fluorescent in situ
hybridization (FISH) with paints for chromosomes 8, 15, and 17 confirmed
the presence of structurally intact chromosomes 15 and 17 and trisomy for
chromosome 8q. Nevertheless, FISH using cosmid probes for PML and RARA
showed their juxtaposition on one chromosome 15 homolog. Both genes were
also present on their normal homologs; in addition, part of the RARA gene
was still present on the remaining chromosome 17. DNA analysis by Southern
blotting, performed with a variety of probes including PML, RARA and
retinoic acid receptor-beta (RARB), showed a rearrangement in PML. Reverse
transcriptase polymerase chain reaction (RT-PCR) confirmed the existence of
hybrid transcripts of 276, 455 bp and 623 bp, from PML- RARA on the der(15)
chromosome, consistent with alternate exon splicing of the long form of the
transcript occurring in 50% to 60% of patients with APL. Our results show
that APL patients with cytogenetically normal chromosomes 15 and 17 may,
nevertheless, have involvement of both PML and RARA genes defining a
subgroup of APL, t(15;17)- negative/PML-RARA-positive which is analogous to
Philadelphia chromosome-negative/BCR-ABL-positive CML. In this case, the
presence of chimeric transcripts suggests that treatment with all-trans RA
may be warranted in APL, even in the absence of detectable cytogenetic
change, showing the usefulness of RT-PCR or FISH to aid diagnosis.
Volume 83,
Issue 10,
pp. 2946-2951,
05/15/1994
Copyright © 1994 by The American Society of Hematology
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