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Erschienen in: Journal of Hematology & Oncology 1/2014

Open Access 01.12.2014 | Letter to the Editor

8q24 amplified segments involve novel fusion genes between NSMCE2 and long noncoding RNAs in acute myelogenous leukemia

verfasst von: Yoshiaki Chinen, Natsumi Sakamoto, Hisao Nagoshi, Tomohiko Taki, Saori Maegawa, Shotaro Tatekawa, Taku Tsukamoto, Shinsuke Mizutani, Yuji Shimura, Mio Yamamoto-Sugitani, Tsutomu Kobayashi, Yosuke Matsumoto, Shigeo Horiike, Junya Kuroda, Masafumi Taniwaki

Erschienen in: Journal of Hematology & Oncology | Ausgabe 1/2014

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Abstract

The pathogenetic roles of 8q24 amplified segments in leukemic cells with double minute chromosomes remain to be verified. Through comprehensive molecular analyses of 8q24 amplicons in leukemic cells from an acute myelogenous leukemia (AML) patient and AML-derived cell line HL60 cells, we identified two novel fusion genes between NSMCE2 and long noncoding RNAs (lncRNAs), namely, PVT1-NSMCE2 and BF104016-NSMCE2. Our study suggests that 8q24 amplicons are associated with the emergence of aberrant chimeric genes between NSMCE2 and oncogenic lncRNAs, and also implicate that the chimeric genes involving lncRNAs potentially possess as-yet-unknown oncogenic functional roles.
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Electronic supplementary material

The online version of this article (doi:10.​1186/​s13045-014-0068-2) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.
Abkürzungen
dmins
Double minute chromosomes
hsr
Homogeneously staining regions
FISH
Fluorescence in situ hybridization
lncRNAs
Long noncoding RNAs
AML
Acute myeloid leukemia
MDS
Myelodysplastic syndromes
NSMCE2
Non-SMC element 2
SKY
Spectral karyotyping
RT-PCR
Reverse transcription-polymerase chain reaction
LDI-PCR
Long-distance inverse PCR

To the Editor

To gain insight into the role(s) of double minute chromosomes (dmins) in leukemia, we cytogenetically/molecularly analyzed 8q24 amplicons in patient-derived leukemic cells and AML-derived cell line (HL60) (See Additional file 1 for supplementary materials and methods). The patient was a 71-year-old female with AML (M2). The G-banding karyotype of leukemic cells was 47, XX, +mar [2]/48, XX, idem, +mar [6]/46, XX [7], containing two marker chromosomes (mars) from chromosome 8 (Figure 1a and b). DNA copy number analysis (CNA) revealed 13 high-level amplicons on 8q22.1-q24.2 (98.43 Mb-134.16 Mb) (Additional file 2: Table S1). SKY analysis of HL60 cells containing the 8q24 amplicons revealed that the representative karyotype was 44, X, der(5)t(5;17)(q11.2;q11.2), t(7;16;9)(q34;q24;p21), t(9;14)(q22;q22), +13, -15, -17, der(21)t(15;21)(q22;q21) [1]. CNA revealed several amplicons on 8q24.13-q24.12 (126.25 Mb-130.75 Mb) in the HL60 cells (Figure 2a and b). Consequently, three common amplicons were identified between 8q24.13-21 in the patient and the HL60 cells; i.e., the regions covering NSMCE2 (8q24.13), PVT1 (8q24.21) and CCDC26 (8q24.21) (Figures 1c and 2b). Further investigation revealed three fusion transcripts between PVT1 exon 1a and NSMCE2 exon 3 in the patient (Figure 1d and e), and a fusion gene between exon 6 of NSMCE2 and exon 1 of BF104016, a noncoding RNA sharing the sequence of CCDC26 exon 4 (Additional file 3: Figure S1) (Additional file 4: Table S2), in the HL60 cells (Figure 2c-e). Both the NSMCE2 and PVT1 genes were amplified and located in a micronucleus in the patient (Figure 1f-i), and the genomic junction of 5’-PVT1-NSMCE2-3’ was located within intron 1 of PVT1 and at 5’ upstream of exon 1 of NSMCE2 (Figure 1j and k) (Additional file 5: Figure S3). In the HL60 cells, amplification of 3’NSMCE2 and 5’CCDC26 was co-localized on der(13)hsr(8), ins(2;8) and dmins (Figure 2e-h) (Additional file 5: Figure S3). Aberrant NSMCE2 transcripts were higher than normal NSMCE2 transcripts in the patient and the HL60 cells, while NSMCE2 protein expression did not correlate with normal or abnormal NSMCE2 transcripts among the leukemic patient cells or the HL60 cells, suggesting the presence of regulatory mechanisms other than transcription (Additional file 6: Figure S2).
The present findings are consistent with previous studies demonstrating that segmental genome amplification of 8q24 contains recurrent PVT1 fusion genes, which might be generated by chromothripsis [2],[3]. Both lncRNAs, PVT1 and CCDC26, harbor retroviral integration sites and are transcribed into multiple splice forms [4]-[6]. PVT1 overexpression is induced by MYC or p53, contributing to suppression of apoptosis [7]-[9], whereas PVT1 produces six annotated microRNAs that have been implicated in oncogenesis [3],[10],[11]. The chimeric transcripts involving PVT1 may also regulate the expression of as-yet unspecified target genes through ‘enhancer-like functions’ [12]. CCDC26 amplification has been also identified as a recurrent abnormality that is associated with the response to retinoic acid-induced differentiation in AML [1],[11],[13]-[16]. This study is the first to identify NSMCE2-associated fusion genes in AML [17]-[19]. Knockdown of NSMCE2 induces chromosomal instability and increases the frequency of chromosomal breakage and loss [20]. We speculate that NSMCE2 gene rearrangement may potentially influence its function. Collectively, our study identified novel PVT1-NSMCE2 and CCDC26-NSMCE2 fusion genes that may play functional roles in leukemia.

Authors’ contributions

YC, JK and MT reviewed the literature and wrote the paper. YC, MYS, SM, and SH treated the patient. NS, HN, TT, SM, ST, TT, YS, TK, YM and MT collected the data. YC and NS performed the molecular analyses. YC, JK and MT contributed to the design of this study, final data analysis and edited the manuscript. All authors read and approved the final manuscript.

Additional files

Acknowledgements

The authors thank Akari Kazami and Yoko Yamane for their expert technical assistance. This study was performed as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan, and supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan, by a Grant-in-aid for Scientific Research (B) and (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the National Cancer Center Research and Development Fund.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
The Creative Commons Public Domain Dedication waiver (https://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Competing interests

The authors declare that they have no competing interests.

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Metadaten
Titel
8q24 amplified segments involve novel fusion genes between NSMCE2 and long noncoding RNAs in acute myelogenous leukemia
verfasst von
Yoshiaki Chinen
Natsumi Sakamoto
Hisao Nagoshi
Tomohiko Taki
Saori Maegawa
Shotaro Tatekawa
Taku Tsukamoto
Shinsuke Mizutani
Yuji Shimura
Mio Yamamoto-Sugitani
Tsutomu Kobayashi
Yosuke Matsumoto
Shigeo Horiike
Junya Kuroda
Masafumi Taniwaki
Publikationsdatum
01.12.2014
Verlag
BioMed Central
Erschienen in
Journal of Hematology & Oncology / Ausgabe 1/2014
Elektronische ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-014-0068-2

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