Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Gene structure, expression profiling and mutation analysis of the tumour suppressor SHIP1 in Caucasian acute myeloid leukaemia

Leukemia volume 21, pages 2390–2393 (2007)Cite this article

The phosphatidylinositol-3-kinase–Akt (PI3K–Akt) signalling pathway plays a critical role in regulating the cellular processes of growth, survival and differentiation. Constitutive activation of the pathway is recognized to be heavily implicated in the development of cancer. Mutation of members of the PI3K–Akt pathway is observed in up to 30% of all human cancers, and the PI3K–Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells. Furthermore, constitutive Akt phosphorylation is linked to drug resistance and shortened overall survival in AML. Appropriate and timely negative regulation of the PI3K pathway is required to avoid constitutive signalling.

We aimed to determine the incidence of INPP5D mutations in a cohort of 57 Caucasian AML patients, representing all eight French–American–British (FAB) subtypes (M0–M7), by denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing. At the outset of our study, we noted that human INPP5D was poorly characterized in the literature and on genome databases. We therefore interpreted INPP5D gene structure based on alignment between INPP5D transcript (cDNA accession U57650) and human chromosome 2 assembled sequences. We found human INPP5D to consist of 27 exons, spanning a genomic region of at least 148 kb of chromosome 2q37.1 (Figure 1). All 27 exons are flanked by canonical AG (acceptor) and GT (donor) splice sites. Exons range in size from 64 bp (exon 2) to 1196 bp (exon 27, including the 3′ untranslated region (UTR), and introns (with the exception of intron 5, whose length is yet to be determined) from 125 bp to 42.7 kb. A small CpG island comprising 18 CpGs within a 227-bp region of the first exon was identified. In the absence of any evidence for an additional 5′ untranslated exon, it appears that INPP5D is transcribed using a TATA-less promoter.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Helgason CD, Damen JE, Rosten P, Grewal R, Sorensen P, Chappel SM et al. Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev 1998; 12: 1610–1620.

    Article  CAS  Google Scholar 

  2. Luo JM, Yoshida H, Komura S, Ohishi N, Pan L, Shigeno K et al. Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia. Leukemia 2003; 17: 1–8.

    Article  CAS  Google Scholar 

  3. Luo JM, Liu ZL, Hao HL, Wang FX, Dong ZR, Ohno R . Mutation analysis of SHIP gene in acute leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2004; 12: 420–426.

    CAS  PubMed  Google Scholar 

  4. Wang Z, Moult J . SNPs, protein structure, and disease. Hum Mutat 2001; 17: 263–270.

    Article  Google Scholar 

  5. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.

    Article  CAS  Google Scholar 

  6. Shigematsu H, Gazdar AF . Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006; 118: 257–262.

    Article  CAS  Google Scholar 

  7. Masri MA, Abdel Seed NM, Fahal AH, Romano M, Baralle F, El Hassam AM et al. Minor role for BRCA2 (exon11) and p53 (exon 5–9) among Sudanese breast cancer patients. Breast Cancer Res Treat 2002; 71: 145–147.

    Article  CAS  Google Scholar 

  8. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004; 350: 1617–1628.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Royal Hallamshire Hospital Leukaemia and Myeloma Research Fund for funding this work and Dr I Brock, University of Sheffield Cancer Studies Institute for DHPLC operation and analysis. The authors are grateful to Professor DC Linch and Mr S Langabeer for provision of DNA from patients entered into the Medical Research Council Trails AML X and XII.

Author information

Authors and Affiliations

  1. Academic Unit of Haematology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK

    D C Gilby, A C Goodeve, P R Winship & J T Reilly

  2. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    P J Valk & R Delwel

Authors
  1. D C Gilby
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A C Goodeve
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P R Winship
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P J Valk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Delwel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J T Reilly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J T Reilly.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gilby, D., Goodeve, A., Winship, P. et al. Gene structure, expression profiling and mutation analysis of the tumour suppressor SHIP1 in Caucasian acute myeloid leukaemia. Leukemia 21, 2390–2393 (2007). https://doi.org/10.1038/sj.leu.2404864

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404864

This article is cited by

Search

Advanced search

Quick links