A Case of a Novel PML/RARA Short Fusion Transcript with Truncated Transcription Variant 2 of the RARA Gene
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CASE REPORT
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A Case of a Novel PML/RARA Short Fusion Transcript with Truncated Transcription Variant 2 of the RARA Gene Ivana Jezˇ´ısˇkova´,1 Filip Ra´zga,1 Jana Gazdova´,1 Michael Doubek,2 Toma´sˇ Jurcˇek,1 Zdeneˇk Korˇ´ıstek,2 Jirˇ´ı Mayer2 and Dana Dvorˇa´kova´1 1 Center of Molecular Biology and Gene Therapy, Department of Internal Medicine–Hemato-oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic 2 Department of Internal Medicine–Hemato-oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
Abstract
Acute promyelocytic leukemia (APL) with atypical breakpoints in the promyelocytic leukemia (PML) and retinoic acid receptor-a (RARA) genes represents a rare leukemic event, which occurs preferentially in patients with variant types of the PML/RARA fusion gene. Here we report on a patient with APL with a unique PML/RARA fusion transcript that harbors a short type of this fusion gene, exhibiting unexpected results of standard PCR diagnostics. The detected transcript originates from fusion of PML exon 4 and a truncated form of transcription variant 2 of the RARA gene, with an additional 9 bp insertion. According to our knowledge, this differs from all previously described fusion transcripts.
1. Background Acute promyelocytic leukemia (APL) accounts for approximately 10% of newly diagnosed acute myeloid leukemias (AML).[1] The balanced reciprocal translocation t(15;17)(q22;q12), leading to fusion of the promyelocytic leukemia gene (PML) on chromosome 15 and the retinoic acid receptor-a gene (RARA) on chromosome 17, is detected in more than 99% of all APL cases.[1,2] Both PML/RARA and RARA/PML fusion transcripts originate from such translocation, but only the PML/RARA fusion gene is present in all t(15;17) APL patients, in contrast to RARA/PML, which is detected in only 81% of APL patients.[3] Considering this, the PML/RARA fusion gene is more suitable for APL detection on the molecular level. However, parallel use of a reciprocal RARA/PML assay increases the rates of minimal residual disease detection in APL patients.[4] At the messenger RNA level, three basic types of PML/RARA fusion transcripts have been classified – long, short, and variant type (figure 1). The breakpoint on chromosome 17 is consistently located within intron 2 of the RARA gene, and therefore the difference between individual fusion types is determined by a breakpoint region in the PML gene on chromosome 15. The long PML/RARA fusion type is expressed
in approximately 55% of patients with APL and results from the fusion of PML exon 6 and RARA exon 3 (figure 1a). About PML a
RARA
Long fusion type Exon
1
2
3
4
5
6
M2 ENF903
3
4
5
ENR962 R8 ENP942
b Variant fusion type Exon 1
2
3
4
5
6
ENF906 c
3
4
5
ENR962 ENP942
Short fusion type Exon
1
2
3 M4 ENF905
3
4 5 ENR962 R8 ENP942
Fig. 1. The three basic types of the promyelocytic leukemia/retinoic acid receptor-a (PML/RARA) fusion gene – (a) long, (b) variant, and (c)
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