Acute promyelocytic leukaemia with PML-RARA fusion is usually associated with the t(15;17)(q24.1;q21.1) translocation but may also arise from complex or cryptic rearrangements. The fusion usually resides on chromosome 15 but occasionally on others. We describe a cryptic PML-RARA fusion within a novel chromosome 17 rearrangement. We performed interphase fluorescence in situ hybridisation (FISH) using a dual-fusion PML-RARA probe, followed by reverse transcriptase-polymerase chain reaction (RT-PCR) for PML-RARA, karyotyping, and metaphase FISH using RARA break-apart, locus-specific, and subtelomere probes for chromosome 17. An 850K SNP microarray was also employed. Interphase and metaphase FISH showed atypical results involving a single PML-RARA fusion, no second fusion, but instead separate diminished PML and RARA signals. RT-PCR confirmed PML-RARA fusion; however, karyotyping detected only an altered chromosome 17. Metaphase FISH showed the single fusion and diminished 5′ RARA signals located unexpectedly in the subtelomeric short-arm and long-arm regions of the rearranged chromosome 17, respectively. SNP microarray revealed no copy number abnormality. This paediatric patient with PML-RARA fusion reflects a cryptic insertion that resides within a complex and novel chromosome 17 rearrangement. This rearrangement likely arose via 7 chromosome breaks with the insertion occurring first followed by sequential paracentric and then pericentric inversions.

Adams J, Nassiri M: Acute promyelocytic leukemia: a review and discussion of variant translocations. Arch Pathol Lab Med 139:1308-1313 (2015).
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, et al: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391-2405 (2016).
Beitinjaneh A, Jang S, Roukoz H, Majhail NS: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: a systematic review. Leuk Res 34:831-836 (2010).
Breccia M, Loglisci G, Loglisci MG, Ricci R, Diverio D, et al: FLT3-ITD confers poor prognosis in patients with acute promyelocytic leukemia treated with AIDA protocols: long-term follow-up analysis: Haematologica 98:e161-163 (2013).
Chatterjee T, Gupta S, Sharma S, Ganguli P: Distribution of different PML/RARalpha bcr isoforms in Indian acute promyelocytic leukemia (APL) patients and clinicohematological correlation. Mediterr J Hematol Infect Dis 6:e2014004 (2014).
Cheng Y, Zhang L, Wu J, Lu A, Wang B, Liu G: Long-term prognosis of childhood acute promyelocytic leukaemia with arsenic trioxide administration in induction and consolidation chemotherapy phases: a single-centre experience. Eur J Haematol 91:483-489 (2013).
De Braekeleer E, Douet-Guilbert N, De Braekeleer M: RARA fusion genes in acute promyelocytic leukemia: a review. Expert Rev Hematol 7:347-357 (2014).
Grimwade D, Gorman P, Duprez E, Howe K, Langabeer S, et al: Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. Blood 90:4876-4885 (1997).
Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, et al: Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Francais de Cytogenetique Hematologique, Groupe de Francais d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action “Molecular Cytogenetic Diagnosis in Haematological Malignancies”. Blood 96:1297-1308 (2000).
Guan H, Liu J, Guo X, Wu C, Yu H: Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): a case report and review of the literature. Exp Ther Med 10:1009-1012 (2015).
Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, et al: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567-572 (1988).
ISCN 2016: An International System for Human Cytogenomic Nomenclature; in McGowan-Jordan J, Simons A, Schmid M (eds). Cytogenet Genome Res 149:1-140 (2016).
Knight SJ, Lese CM, Precht KS, Kuc J, Ning Y, et al: An optimized set of human telomere clones for studying telomere integrity and architecture. Am J Hum Genet 67:320-332 (2000).
Kutny MA, Moser BK, Laumann K, Feusner JH, Gamis A, et al: FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 59:662-667 (2012).
Lee GY, Christina S, Tien SL, Ghafar AB, Hwang W, et al: Acute promyelocytic leukemia with PML-RARA fusion on i(17q) and therapy-related acute myeloid leukemia. Cancer Genet Cytogenet 159:129-136 (2005).
Liu Y, Chen YT, Li JX, Zhang SH: Immunophenotypic analysis of leukemia promyelocytes in 71 patients with acute promyelocytic leukemia (in Chinese). Zhongguo Shi Yan Xue Ye Xue Za Zhi 20:806-811 (2012).
Long ZJ, Hu Y, Li XD, He Y, Xiao RZ, et al: ATO/ATRA/anthracycline-chemotherapy sequential consolidation achieves long-term efficacy in primary acute promyelocytic leukemia. PLoS One 9:e104610 (2014).
Molica M, Breccia M: FLT3-ITD in acute promyelocytic leukemia: clinical distinct profile but still controversial prognosis. Leukemia Res 39:397-399 (2015).
Ravandi F, Estey EH, Appelbaum FR, Lo-Coco F, Schiffer CA, et al: Gemtuzumab ozogamicin: time to resurrect? J Clin Oncol 30:3921-3923 (2012).
Schnittger S, Bacher U, Kern W, Alpermann T, Haferlach C, Haferlach T: Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia. Leukemia 25:1297-1304 (2011).
Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, et al: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 101:5328-5335 (2004).
Testa U, Lo-Coco F: Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients. Ann Hematol 95:673-680 (2016).
Testi AM, D'Angio M, Locatelli F, Pession A, Lo Coco F: Acute promyelocytic leukemia (APL): comparison between children and adults. Mediterr J Hematol Infect Dis 6:e2014032 (2014).
Wan TS, Ma SK, Yip SF, Yeung YM, Chan LC: Molecular characterization of der(15)t(11;15) as a secondary cytogenetic abnormality in acute promyelocytic leukemia with cryptic PML-RAR alpha fusion on 17q. Cancer Genet Cytogenet 121:90-93 (2000).
Wang HY, Ding J, Vasef MA, Wilson KS: A bcr3/short form PML-RAR alpha transcript in an acute promyelocytic leukemia resulted from a derivative chromosome 17 due to submicroscopic insertion of the PML gene into the RAR alpha locus. Am J Clin Pathol 131:64-71 (2009).
Webber LM, Garson OM: Fluorodeoxyuridine synchronization of bone marrow cultures. Cancer Genet Cytogenet 8:123-132 (1983).
Welch JS, Westervelt P, Ding L, Larson DE, Klco JM, et al: Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. JAMA 305:1577-1584 (2011).
Wong KF, Chow E, Siu LL, Wong WS: Acute promyelocytic leukaemia with cryptic PML-RARA fusion. Br J Haematol 145:2 (2009).
Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19:1345-1349 (2005).
Zaccaria A, Valenti A, Toschi M, Salvucci M, Cipriani R, et al: Cryptic translocation of PML/RARA on 17q. A rare event in acute promyelocytic leukemia. Cancer Genet Cytogenet 138:169-173 (2002).
Zhang L, Samad A, Pombo-de-Oliveira MS, Scelo G, Smith MT, et al: Global characteristics of childhood acute promyelocytic leukemia. Blood Rev 29:101-125 (2015).
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.