Cryptic FUS-ERG fusion identified by RNA-sequencing in childhood acute myeloid leukemia

Panagopoulos,Ioannis; Gorunova,Ludmila; Zeller,Bernward; Tierens,Anne; Heim,Sverre

doi:10.3892/or.2013.2751

Cryptic FUS-ERG fusion identified by RNA-sequencing in childhood acute myeloid leukemia

Authors:
- Ioannis Panagopoulos
- Ludmila Gorunova
- Bernward Zeller
- Anne Tierens
- Sverre Heim
View Affiliations

Affiliations: Section for Cancer Cytogenetics, Institute for Medical Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway, Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway, Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital; 5Faculty of Medicine, University of Oslo, Oslo, Norway
Published online on: September 25, 2013 https://doi.org/10.3892/or.2013.2751
Pages: 2587-2592
Copyright: © Panagopoulos et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Sequential combination of cytogenetics and RNA-sequencing (RNA-Seq) has been shown to be an efficient approach to detect pathogenetically important fusion genes in neoplasms carrying only one or a few chromosomal rearrangements. We performed RNA-Seq on an acute myeloid leukemia in a 2-year-old girl with the karyotype 46,XX,add(1)(p36), der(2)t(2;3)(q21;q21),del(3)(q21),der(10)t(1;10)(q32;q24),der(16)(2qter-->2q21::16p11-->16q24::16p11-->16pter)[13]/46,XX[2] and identified a cryptic FUS/ERG fusion gene. PCR and direct sequencing verified the presence of the FUS-ERG chimeric transcript in which exon 7 of FUS from 16p11 (nt 904 in sequence with accession number NM_004960 version 3) was fused in frame to exon 8 of ERG from sub-band 21q22.2 (nt 967 in NM_004449 version 4). The FUS-ERG transcript found here has been reported in only two other cases of childhood leukemia, in a 1-year-old boy and an 8-month-old boy, both diagnosed with precursor B cell ALL. The fusion transcript codes for a 497 amino acid residues FUS-ERG protein and, similar to other AML-related FUS-ERG fusion proteins, contains both functional domains (TR1 and TR2) of the transactivation domain of FUS and the ETS domain of ERG. The clinical significance, if any, of the amino acid residues which are coded by the exons 8, 9 and 10 of ERG in the fusion FUS-ERG proteins, remains unclear.

View Figures

View References

1	Ichikawa H, Shimizu K, Hayashi Y and Ohki M: An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Cancer Res. 54:2865–2868. 1994.PubMed/NCBI
2	Panagopoulos I, Aman P, Fioretos T, et al: Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22). Genes Chromosomes Cancer. 11:256–262. 1994. View Article : Google Scholar : PubMed/NCBI
3	Fukushima Y, Fujii N, Tabata Y, et al: AML(M7) associated with t(16;21)(p11;q22) showing relapse after unrelated bone marrow transplantation and disappearance of TLS/FUS-ERG mRNA. Rinsho Ketsueki. 42:502–506. 2001.PubMed/NCBI
4	Kong XT, Ida K, Ichikawa H, et al: Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t(16;21)(p11;q22) and identification of a novel transcript. Blood. 90:1192–1199. 1997.PubMed/NCBI
5	Kanazawa T, Ogawa C, Taketani T, Taki T, Hayashi Y and Morikawa A: TLS/FUS-ERG fusion gene in acute lymphoblastic leukemia with t(16;21)(p11;q22) and monitoring of minimal residual disease. Leuk Lymphoma. 46:1833–1835. 2005. View Article : Google Scholar : PubMed/NCBI
6	Manola KN, Georgakakos VN, Stavropoulou C, et al: Jumping translocations in hematological malignancies: a cytogenetic study of five cases. Cancer Genet Cytogenet. 187:85–94. 2008. View Article : Google Scholar : PubMed/NCBI
7	Pereira DS, Dorrell C, Ito CY, et al: Retroviral transduction of TLS-ERG initiates a leukemogenic program in normal human hematopoietic cells. Proc Natl Acad Sci USA. 95:8239–8244. 1998. View Article : Google Scholar : PubMed/NCBI
8	Berg T, Kalsaas AH, Buechner J and Busund LT: Ewing sarcoma-peripheral neuroectodermal tumor of the kidney with a FUS-ERG fusion transcript. Cancer Genet Cytogenet. 194:53–57. 2009. View Article : Google Scholar : PubMed/NCBI
9	Shing DC, McMullan DJ, Roberts P, et al: FUS/ERG gene fusions in Ewing’s tumors. Cancer Res. 63:4568–4576. 2003.PubMed/NCBI
10	Zou J, Ichikawa H, Blackburn ML, et al: The oncogenic TLS-ERG fusion protein exerts different effects in hematopoietic cells and fibroblasts. Mol Cell Biol. 25:6235–6246. 2005. View Article : Google Scholar : PubMed/NCBI
11	Shimizu K, Ichikawa H, Tojo A, et al: An ets-related gene, ERG, is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation. Proc Natl Acad Sci USA. 90:10280–10284. 1993. View Article : Google Scholar : PubMed/NCBI
12	Sorensen PH, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ and Denny CT: A second Ewing’s sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet. 6:146–151. 1994.
13	Zucman J, Melot T, Desmaze C, et al: Combinatorial generation of variable fusion proteins in the Ewing family of tumours. EMBO J. 12:4481–4487. 1993.PubMed/NCBI
14	Crozat A, Aman P, Mandahl N and Ron D: Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 363:640–644. 1993. View Article : Google Scholar : PubMed/NCBI
15	Rabbitts TH, Forster A, Larson R and Nathan P: Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet. 4:175–180. 1993. View Article : Google Scholar : PubMed/NCBI
16	Maher CA, Kumar-Sinha C, Cao X, et al: Transcriptome sequencing to detect gene fusions in cancer. Nature. 458:97–101. 2009. View Article : Google Scholar : PubMed/NCBI
17	Tanas MR, Sboner A, Oliveira AM, et al: Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med. 3:98ra822011. View Article : Google Scholar : PubMed/NCBI
18	Lee CH, Ou WB, Marino-Enriquez A, et al: 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma. Proc Natl Acad Sci USA. 109:929–934. 2012. View Article : Google Scholar : PubMed/NCBI
19	Panagopoulos I, Thorsen J, Gorunova L, et al: Fusion of the ZC3H7B and BCOR genes in endometrial stromal sarcomas carrying an X;22-translocation. Genes Chromosomes Cancer. 52:610–618. 2013.PubMed/NCBI
20	Nyquist KB, Panagopoulos I, Thorsen J, et al: Whole-transcriptome sequencing identifies novel IRF2BP2-CDX1 fusion gene brought about by translocation t(1;5)(q42;q32) in mesenchymal chondrosarcoma. PLoS One. 7:e497052012. View Article : Google Scholar : PubMed/NCBI
21	Panagopoulos I, Thorsen J, Gorunova L, et al: RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12). Genes Chromosomes Cancer. 52:733–740. 2013. View Article : Google Scholar : PubMed/NCBI
22	Micci F, Thorsen J, Haugom L, Zeller B, Tierens A and Heim S: Translocation t(1;16)(p31;q24) rearranging CBFA2T3 is specific for acute erythroid leukemia. Leukemia. 25:1510–1512. 2011. View Article : Google Scholar : PubMed/NCBI
23	Micci F, Thorsen J, Panagopoulos I, et al: High-throughput sequencing identifies an NFIA/CBFA2T3 fusion gene in acute erythroid leukemia with t(1;16)(p31;q24). Leukemia. 27:980–982. 2013. View Article : Google Scholar : PubMed/NCBI
24	Panagopoulos I, Micci F, Thorsen J, et al: Fusion of ZMYND8 and RELA genes in acute erythroid leukemia. PLoS One. 8:e636632013. View Article : Google Scholar : PubMed/NCBI
25	Abrahamsson J, Forestier E, Heldrup J, et al: Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol. 29:310–315. 2011. View Article : Google Scholar : PubMed/NCBI
26	Schaffer LG, Slovak ML and Campbell LJ: ISCN 2009: an International System for Human Cytogenetic Nomenclature. Karger; Basel: 2009
27	Ge H, Liu K, Juan T, Fang F, Newman M and Hoeck W: FusionMap: detecting fusion genes from next-generation sequencing data at base-pair resolution. Bioinformatics. 27:1922–1928. 2011. View Article : Google Scholar : PubMed/NCBI
28	Duhoux FP, Ameye G, Montano-Almendras CP, et al: PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 156:76–88. 2012. View Article : Google Scholar : PubMed/NCBI
29	Gamou T, Kitamura E, Hosoda F, et al: The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. Blood. 91:4028–4037. 1998.PubMed/NCBI
30	Gruber TA, Larson Gedman A, Zhang J, et al: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell. 22:683–697. 2012. View Article : Google Scholar : PubMed/NCBI
31	Oh SH, Park TS, Choi JR, et al: Two childhood cases of acute leukemia with t(16;21)(p11.2;q22): second case report of infantile acute lymphoblastic leukemia with unusual type of FUS-ERG chimeric transcript. Cancer Genet Cytogenet. 200:180–183. 2010. View Article : Google Scholar : PubMed/NCBI
32	Ichikawa H, Shimizu K, Katsu R and Ohki M: Dual transforming activities of the FUS (TLS)-ERG leukemia fusion protein conferred by two N-terminal domains of FUS (TLS). Mol Cell Biol. 19:7639–7650. 1999.PubMed/NCBI