Skip to main content

Advertisement

SpringerLink
Log in

RNA-Seq analysis identifies aberrant RNA splicing of TRIP12 in acute myeloid leukemia patients at remission

  • Research Article
  • Published:
Tumor Biology

Abstract

Aberrant splicing events play important roles in the pathogenesis of acute myeloid leukemia (AML). To investigate the aberrant splicing events in AML during treatment, we carried out RNA sequencing in peripheral mononuclear cell samples from a patient with complete remission. In addition to the sequencing samples, selected splicing events were confirmed and validated with real-time quantitative RT-PCR in another seven pairs of samples. A total of 4.05 and 3.39 GB clean data of the AML and remission sample were generated, respectively, and 2,223 differentially expressed genes (DEGs) were identified. Integrated with gene expression profiling on T cells from AML patients compared with healthy donors, 82 DEGs were also differentially expressed in AML CD4 T cells and CD8 T cells. Twenty-three alternative splicing events were considered to be confidential, and they were involved in many biological processes, such as RNA processing, cellular macromolecule catabolic process, and DNA binding process. An exon3-skipping event in TRIP12 was detected in patients at remission and further validated in another three independent samples. TRIP12 is an ubiquitin ligase of ARF, which suppresses aberrant cell growth by activating p53 responses. The exon3-skipping isoform of TRIP12 increased significantly after treatment. Our results may provide new understanding of AML, and the confirmed alternative splicing event of TRIP12 may be used as potential target for future investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Marcucci G, Haferlach T, Dohner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29:475–86.

    Article  CAS  PubMed  Google Scholar 

  2. Deschler B, Lubbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer. 2006;107:2099–107.

    Article  PubMed  Google Scholar 

  3. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Frohling S, Scholl C, Gilliland DG, Levine RL. Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol. 2005;23:6285–95.

    Article  CAS  PubMed  Google Scholar 

  5. Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaemia—a review. Br J Haematol. 2008;140:123–32.

    Article  CAS  PubMed  Google Scholar 

  6. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–18.

    Article  CAS  PubMed  Google Scholar 

  7. Liu X, Zhang Q, Zhang DE, Zhou C, Xing H, Tian Z, et al. Overexpression of an isoform of AML1 in acute leukemia and its potential role in leukemogenesis. Leukemia. 2009;23:739–45.

    Article  CAS  PubMed  Google Scholar 

  8. Mannari D, Gascoyne D, Dunne J, Chaplin T, Young B. A novel exon in AML1-ETO negatively influences the clonogenic potential of the t(8;21) in acute myeloid leukemia. Leukemia. 2010;24:891–4.

    Article  CAS  PubMed  Google Scholar 

  9. Ommen HB, Ostergaard M, Yan M, Braendstrup K, Zhang DE, Hokland P. Persistent altered fusion transcript splicing identifies RUNX1-RUNX1T1+ AML patients likely to relapse. Eur J Haematol. 2010;84:128–32.

    Article  CAS  PubMed  Google Scholar 

  10. Vassen L, Khandanpour C, Ebeling P, van der Reijden BA, Jansen JH, Mahlmann S, et al. Growth factor independent 1b (Gfi1b) and a new splice variant of Gfi1b are highly expressed in patients with acute and chronic leukemia. Int J Hematol. 2009;89:422–30.

    Article  CAS  PubMed  Google Scholar 

  11. Kote-Jarai Z. Amin Al Olama A, Leongamornlert D, Tymrakiewicz M, Saunders E, Guy M, Giles GG, Severi G, Southey M, Hopper JL, et al: Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. Hum Genet. 2011;129:687–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, et al. CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest. 2011;121:1064–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Katz Y, Wang ET, Airoldi EM, Burge CB. Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods. 2010;7:1009–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 2012;7:562–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10:R25.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Thorvaldsdottir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013;14:178–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.

    Article  CAS  Google Scholar 

  20. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4:249–64.

    Article  PubMed  Google Scholar 

  21. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57:289–300.

    Google Scholar 

  22. Ogawa S. Splicing factor mutations in myelodysplasia. Int J Hematol. 2012;96:438–42.

    Article  CAS  PubMed  Google Scholar 

  23. Chen D, Yoon JB, Gu W. Reactivating the ARF-p53 axis in AML cells by targeting ULF. Cell Cycle. 2010;9:2946–51.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Collado M, Serrano M. The TRIP from ULF to ARF. Cancer Cell. 2010;17:317–8.

    Article  CAS  PubMed  Google Scholar 

  25. Dunna NR, Vure S, Sailaja K, Surekha D, Raghunadharao D, Rajappa S, et al. TP53 codon 72 polymorphism and risk of acute leukemia. Asian Pac J Cancer Prev: APJCP. 2012;13:347–50.

    Article  PubMed  Google Scholar 

Download references

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Hematology, The Third Hospital Affiliated to Suzhou University, First People’s Hospital of Changzhou, Changzhou, 213003, Jiangsu, China

    Panke Gao, Zhen Jin, Yingying Cheng & Xiangshan Cao

Authors
  1. Panke Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhen Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yingying Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiangshan Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiangshan Cao.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(XLSX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, P., Jin, Z., Cheng, Y. et al. RNA-Seq analysis identifies aberrant RNA splicing of TRIP12 in acute myeloid leukemia patients at remission. Tumor Biol. 35, 9585–9590 (2014). https://doi.org/10.1007/s13277-014-2228-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2228-y

Keywords

Search

Navigation