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Identification of a novel PML-RARG fusion in acute promyelocytic leukemia

Leukemia volume 31, pages 1992–1995 (2017)Cite this article

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The retinoic acid receptor (RAR) is a member of the nuclear receptor family, and has three isoforms: retinoic acid receptor alpha (RARA), retinoic acid receptor beta (RARB) and retinoic acid receptor gamma (RARG). These RARs share a high sequence homology composed of a DNA binding domain (DBD) and a ligand-binding domain (LBD).1 The RARA locus was first demonstrated to be involved in translocation with PML in acute promyelocytic leukemia (APL), in which the newly produced PML-RARA fusion protein behaves as an altered RARA, and represses transcription of retinoic acid (RA) target genes resulting in development of APL. Despite the structural homology among RAR isoforms, human APL case bearing a PML-RARB or PML-RARG fusion has not been reported thus far, although the leukemogenic properties of artificial constructs were confirmed in in vitro and in vivo studies.2, 3 Here we present a novel PML-RARG fusion in a patient with morphologic and immunophenotypic features of classical hypergranular APL.

A BM sample obtained at diagnosis was processed after a short-term (24 h) and un-stimulated culture following standard procedures. Fluorescence in situ hybridization (FISH) studies were performed using a PML-RARA dual-color dual-fusion translocation probe (Abbott Molecular, Des Plaines, IL, USA) according to the manufacturer’s protocols. Multiplex real-time PCR (RT–PCR) was performed using Hemavision (DNA diagnostic A/S, Risskov, Denmark) to detect 29 translocations/chromosomal abnormalities including PML-RARA, PLZF-RARA and NPM1-RARA fusion transcripts. However, the t(15;17)(q22;q22) translocation was not detected by karyotyping; instead, a clonal translocation t(12;15)(q13;q22) was identified in 13 of 20 metaphases analyzed (Figure 1b). Moreover, there was no evidence of PML-RARA or variants PLZF-RARA or NPM1-RARA fusion by RT–PCR. The FISH analysis also showed no PML-RARA fusion signal while PML split signals were found in 485 (97%) out of 500 interphase nuclei. These PML split signals were identified on der(12)t(12;15)(q13;q22) and der(15)t(12;15)(q13;q22) from metaphase FISH and corresponding G-banded chromosomes (Figures 1c and d).

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Acknowledgements

We thank K-S Park, K-S Lee and T-Y Park for good practice performing molecular studies including sequencing and PCR experiments.

Author contributions

J-SH and C-SK designed the molecular studies and wrote the paper; YRD was involved in the management of the patient and providing clinical data; CL analyzed the next-generation sequencing data; D-HK performed cytogenetic analyses and FISH experiments; and D-SJ, N-HR and WL performed morphologic analyses and supervised the molecular studies. All authors read and approved the manuscript.

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Author notes

  1. J-S Ha and Y R Do: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea

    J-S Ha, D-H Kim, W Lee, N-H Ryoo & D-S Jeon

  2. Division of Hemato-Oncology, Department of Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea

    Y R Do

  3. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    C-S Ki

  4. Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea

    C Lee

  5. Department of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea

    C Lee

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  1. J-S Ha
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Correspondence to J-S Ha or C-S Ki.

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Ha, JS., Do, Y., Ki, CS. et al. Identification of a novel PML-RARG fusion in acute promyelocytic leukemia. Leukemia 31, 1992–1995 (2017). https://doi.org/10.1038/leu.2017.167

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