DEK-NUP214 gene fusion in acute myeloid leukemia (AML) is associated with poor prognosis. It is most often a sole translocation and more rarely observed as complex chromosomal forms. We describe an AML case with complex karyotype abnormalities involving chromosome bands 6p23, 6q13, 7p22, and 9q34. RNA sequencing analysis revealed that exon 17 of NUP214 (9q34) was fused to exon 2 of RAC1 (7p22). We also detected that the 5′-end of intron 1 of RAC1 was fused with the antisense strand of intron 5 of COL12A1 (6q13). RT-PCR analysis confirmed the expression of DEK-NUP214, NUP214-RAC1, RAC1-COL12A1, NUP214, and RAC1. These results suggest that the 5′- and 3′-ends of NUP214 from the breakpoint in the same locus were fused to RAC1 and DEK, respectively, and the 5′-end of RAC1 was fused to COL12A1. The reading frame of NUP214 was not matched with RAC1; however, high expression of the RAC1 protein was detected by Western blotting. This study identifies the variant complex fusion genesNUP214-RAC1 and RAC1- COL12A1 in a case of AML.

Keywords:
Acute myeloid leukemia, COL12A1, NUP214, RAC1, RNA-seq, Translocation
1.
Ben Abdelali R, Roggy A, Leguay T, Cieslak A, Renneville A, et al: SET-NUP214 is a recurrent γδ lineage-specific fusion transcript associated with corticosteroid/chemotherapy resistance in adult T-ALL. Blood 123:1860-1863 (2014).
2.
Chi Y, Lindgren V, Quigley S, Gaitonde S: Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia: an overview. Arch Pathol Lab Med 132:1835-1837 (2008).
3.
Gómez del Pulgar T, Benitah SA, Valerón PF, Espina C, Lacal JC: Rho GTPase expression in tumourigenesis: evidence for a significant link. Bioessays 27:602-613 (2005).
4.
Gorello P, La Starza R, Di Giacomo D, Messina M, Puzzolo MC, et al: SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic leukemia. Haematologica 95:2161-2163 (2010).
5.
Graux C, Cools J, Melotte C, Quentmeier H, Ferrando A, et al: Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 36:1084-1089 (2004).
6.
Kataoka T, Morishita Y, Ogura M, Morishima Y, Towatari M, et al: A novel human myeloid leukemia cell line, NKM-1, coexpressing granulocyte colony-stimulating factor receptors and macrophage colony-stimulating factor receptors. Cancer Res 50:7703-7709 (1990).
7.
Kawazu M, Ueno T, Kontani K, Ogita Y, Ando M, et al: Transforming mutations of RAC guanosine triphosphatases in human cancers. Proc Natl Acad Sci USA 110:3029-3034 (2013).
8.
Kraemer D, Wozniak RW, Blobel G, Radu A: The human CAN protein, a putative oncogene product associated with myeloid leukemogenesis, is a nuclear pore complex protein that faces the cytoplasm. Proc Natl Acad Sci USA 91:1519-1523 (1994).
9.
Levin JZ, Berger MF, Adiconis X, Rogov P, Melnikov A, et al: Targeted next-generation sequencing of a cancer transcriptome enhances detection of sequence variants and novel fusion transcripts. Genome Biol 10:R115 (2009).
10.
Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B, et al: Transcriptome sequencing to detect gene fusions in cancer. Nature 458:97-101 (2009).
11.
Slovak ML, Gundacker H, Bloomfield CD, Dewald G, Appelbaum FR, et al: A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare ‘poor prognosis' myeloid malignancies. Leukemia 20:1295-1297 (2006).
12.
Storlazzi CT, Wozniak A, Panagopoulos I, Sciot R, Mandahl N, et al: Rearrangement of the COL12A1 and COL4A5 genes in subungual exostosis: molecular cytogenetic delineation of the tumor-specific translocation t(X;6)(q13-14;q22). Int J Cancer 118:1972-1976 (2006).
13.
Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, et al: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326-4335 (2002).
14.
Wang J, Rao Q, Wang M, Wei H, Xing H, et al: Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth. Biochem Biophys Res Commun 386:769-774 (2009).
15.
Wang Z, Gerstein M, Snyder M: RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10:57-63 (2009).
16.
Weinberg OK, Seetharam M, Ren L, Seo K, Ma L, et al: Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system. Blood 113:1906-1908 (2009).
17.
Yasuda T, Nishio J, Sumegi J, Kapels KM, Althof PA, et al: Aberrations of 6q13 mapped to the COL12A1 locus in chondromyxoid fibroma. Mod Pathol 22:1499-1506 (2009).
18.
Zhou MH, Yang QM: NUP214 fusion genes in acute leukemia (Review). Oncol Lett 8:959-962 (2014).
© 2015 S. Karger AG, Basel
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.