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Genomic analysis of the clonal origin and evolution of acute promyelocytic leukemia in a unique patient with a very late (17 years) relapse

Leukemia volume 28, pages 1751–1754 (2014)Cite this article

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Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by infiltration of abnormal promyelocytes in the bone marrow (BM) and the presence of the balanced reciprocal translocation between the long arms of chromosomes 15 and 17, t(15;17)(q22;q12-21).1 The resulting hybrid PML-RARα gene encodes for a fusion oncoprotein that promotes self-renewal and blocks differentiation at the promyelocyte stage.2 APL was once the most devastating AML subtype because of its coagulopathy, fibrinolysis and rapid death due to internal bleeding. The introduction of all-trans-retinoic acid (ATRA), a cell differentiation inducer, has markedly improved complete remission (CR) rate and overall outcome of patients, and ATRA combined with chemotherapy has become the gold standard for APL therapy.1, 2 Thus, the large majority of CR patients are nowadays long-term survivors and relapses are rarely observed 3 years or more after CR achievement.2, 3 We here report a patient with classic APL who was initially successfully treated with ATRA and chemotherapy; however, after 17 years in CR she again presented with APL. A routine diagnostic work-up did not discriminate between a relapse of her previous APL, the appearance of a secondary APL or a second de novo APL. To elucidate this diagnostic dilemma and define the clonal origin, we performed array-comparative genomic hybridization (CGH) and whole-genome sequencing (WGS) of diagnostic samples from the first and second manifestations of APL and her normal blood cells in CR.

The array-CGH analysis showed that both the initial APL sample and the second one harbored genetic aberrations. An overview of the genetic aberration profiles is shown in Figure 1b. Overlapping between these two samples is very rare, only for a gain of 7p14.1, ∼58 kb and a gain of 14q11.2, ∼484 kb. However, both of these two overlapping regions show copy number variation (CNV) in normal individuals. In addition, there were clear differences in the patterns of aberrations between these two samples—as seen most clearly on chromosomes 19 and 9. The initial APL sample showed a main cluster of discontinuous losses in chromosome 19 (p13.2–p13.11 and q13.11–q13.43), nearly up to 24 Mb, but a small proportion of APL cells harbored chromosome 19 deletion. For the second diagnostic sample, most of the chromosome 9 (p12-p11.2 and q12-q31.1) was lost, ∼16 Mb (Figure 1b). There were more aberrational regions in the initial diagnostic sample than in the second one. Other conspicuous aberrations of the initial diagnostic material were loss of 3p25.1, p21.2–p21.1 (∼2.2 Mb) and gain of 21q22.2.

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Acknowledgements

We thank Dr F Lo Coco (University Tor Vergata, Rome, Italy) for clinical advices. The study was supported by grants from the National Basic Research Program of China (Grant No. 973 Program 2010CB529202 and 2012CB911202), the Adolf H Lundin Charitable Foundation, Swedish Cancer Society, the Swedish Research Council, Cancer Society in Stockholm, and the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet, the National Natural Science Foundation of China (81070224, 81071721, 81000868 and 81171536) and Program for New Century Excellent Talents in University (NCET-10-0555).

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  1. D Xu and M Björkholm: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Department of Medicine, and Center for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden

    X Zhang, J Dahlström, Å Derolf, D Xu & M Björkholm

  2. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China

    Q Zhang

  3. State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University, Shanghai, PR China

    Q Zhang & Z Gu

  4. Department of Clinical Genetics, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

    A N Tran

  5. Computational Intelligence Lab, School of Information Science and Engineering, University of Jinan, Jinan, PR China

    B Yang

  6. Department of Pathology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

    M Ghaderi & A Porwit

  7. Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China

    J Jia

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Corresponding authors

Correspondence to D Xu or M Björkholm.

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Author contributions

Conception and design: X Zhang, Q Zhang, D Xu and M Björkholm; WGS and array-CGH and analysis: Q Zhang, AN Tran, B Yang and Z Gu; acquisition of data: X Zhang; Q Zhang, J Dahlström, Å Derolf, M Ghaderi, A Porwit, D Xu and M Björkholm; analysis and interpretation of data: X Zhang, Q Zhang, AN Tran, J Jia, D Xu and M Björkholm; writing, review and/or revision of the manuscript: X Zhang, Q Zhang, D Xu and M Björkholm.

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Zhang, X., Zhang, Q., Dahlström, J. et al. Genomic analysis of the clonal origin and evolution of acute promyelocytic leukemia in a unique patient with a very late (17 years) relapse. Leukemia 28, 1751–1754 (2014). https://doi.org/10.1038/leu.2014.113

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