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.

  • Original Article
  • Published:

Acute Leukemias

INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia

Leukemia volume 29, pages 1485–1495 (2015)Cite this article

Subjects

Abstract

In this study, we investigated the role of i nositol polyphosphate-4-phosphatase, type-II (INPP4B) in acute myeloid leukemia (AML). We observed that AML patients with high levels of INPP4B (INPP4Bhigh) had poor response to induction therapy, shorter event-free survival and shorter overall survival. Multivariate analyses demonstrated that INPP4Bhigh was an independent predictor of poor prognosis, significantly improving current predictive models, where it outperformed conventional biomarkers including FLT3-ITD and NPM1. Furthermore, INPP4Bhigh effectively segregated relative risk in AML patients with normal cytogenetics. The role of INPP4B on the biology of leukemic cells was assessed in vitro. Overexpression of INPP4B in AML cell lines enhanced colony formation potential, recapitulated the chemotherapy resistance observed in AML patients and promoted proliferation in a phosphatase-dependent, and Akt-independent manner. These findings reveal that INPP4Bhigh has an unexpected role consistent with oncogenesis in AML, in contrast to its previously reported tumor-suppressive role in epithelial cancers. Overall, we propose that INPP4B is a novel prognostic biomarker in AML that has potential to be translated into clinical practice both as a disease marker and therapeutic target.

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

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
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Lowenberg B, Downing JR, Burnett A Acute myeloid leukemia. N Engl J Med 1999; 341: 1051–1062.

    Article  CAS  PubMed  Google Scholar 

  2. Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009; 361: 1249–1259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Walter RB, Othus M, Burnett AK, Löwenberg B, Kantarjian HM, Ossenkoppele GJ et al. Resistance prediction in AML: analysis of 4,601 patients from MRC/NCRI, HOVON/SAKK, SWOG, and MD Anderson Cancer Center. Leukemia 2014; 29: 312–320.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Balla T . Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol Rev 2013; 93: 1019–1137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Park S, Chapuis N, Tamburini J, Bardet V, Cornillet-Lefebvre P, Willems L et al. Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia. Haematologica 2010; 95: 819–828.

    Article  CAS  PubMed  Google Scholar 

  6. Martelli AM, Nyåkern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006; 20: 911–928.

    Article  CAS  PubMed  Google Scholar 

  7. Norris FA, Atkins RC, Majerus PW . The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II. Evidence for conserved alternative splicing in the 4-phosphatase family. J Biol Chem 1997; 272: 23859–23864.

    Article  CAS  PubMed  Google Scholar 

  8. Fedele CG, Ooms LM, Ho M, Vieusseux J, O’Toole SA, Millar EK et al. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci USA 2010; 107: 22231–22236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumour suppressor that inhibits PI3K signaling. Cancer Cell 2009; 16: 115–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hodgson MC, Shao LJ, Frolov A, Li R, Peterson LE, Ayala G et al. Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer. Cancer Res 2011; 71: 572–582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Perez-Lorenzo R, Gill KZ, Shen C-H, Zhao FX, Zheng B, Schulze H-J et al. A tumor suppressor function for the lipid phosphatase INPP4B in melanocytic neoplasms. J Invest Dermatol 2014; 134: 1359–1368.

    Article  CAS  PubMed  Google Scholar 

  12. Stjernström A, Karlsson C, Fernandez OJ, Söderkvist P, Karlsson MG, Thunell LK . Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung. Cancer Med 2014; 3: 337–348.

    Article  PubMed  PubMed Central  Google Scholar 

  13. The Cancer Genome Atlas Research Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61–70.

    Article  Google Scholar 

  14. Westbrook TF, Martin ES, Schlabach MR, Leng Y, Liang AC, Feng B et al. A genetic screen for candidate tumor suppressors identifies REST. Cell 2005; 121: 837–848.

    Article  CAS  PubMed  Google Scholar 

  15. Barnache S, Le Scolan E, Kosmider O, Denis N, Moreau-Gachelin F . Phosphatidylinositol 4-phosphatase type II is an erythropoietin-responsive gene. Oncogene 2006; 25: 1420–1423.

    Article  CAS  PubMed  Google Scholar 

  16. Franke TF, Kaplan DR, Cantley LC, Toker A . Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 1997; 275: 665–668.

    Article  CAS  PubMed  Google Scholar 

  17. Frech M, Andjelkovic M, Ingley E, Reddy KK, Falck JR, Hemmings BA . High affinity binding of inositol phosphates and phosphoinositides to the pleckstrin homology domain of RAC/protein kinase B and their influence on kinase activity. J Biol Chem 1997; 272: 8474–8481.

    Article  CAS  PubMed  Google Scholar 

  18. Klippel A, Kavanaugh WM, Pot D, Williams LT . A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol 1997; 17: 338–344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Salmena L, Shaw P, Fan I, McLaughlin JR, Rosen B, Risch H et al. Prognostic value of INPP4B protein immunohistochemistry in ovarian cancer. Eur J Gynaecol Oncol 2015; doi:10.12892/ejgo2741.2015.

  20. Lundin C, Hjorth L, Behrendtz M, Nordgren A, Palmqvist L, Andersen MK et al. High frequency of BTG1 deletions in acute lymphoblastic leukaemia in children with down syndrome. Genes Chromosomes Cancer 2012; 51: 196–206.

    Article  CAS  PubMed  Google Scholar 

  21. Ross ME, Zhou X, Song G, Shurtleff SA, Girtman K, Williams WK et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 2003; 102: 2951–2959.

    Article  CAS  PubMed  Google Scholar 

  22. Budczies J, Klauschen F, Sinn B V, Győrffy B, Schmitt WD, Darb-Esfahani S et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS One 2012; 7: e51862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Van Galen P, Kreso A, Mbong N, Kent DG, Fitzmaurice T, Chambers JE et al. The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. Nature 2014; 510: 268–272.

    Article  CAS  PubMed  Google Scholar 

  24. Metzeler KH, Hummel M, Bloomfield CD, Spiekermann K, Braess J, Sauerland M-C et al. An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood 2008; 112: 4193–4201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bullinger L, Rücker FG, Kurz S, Du J, Scholl C, Sander S et al. Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. Blood 2007; 110: 1291–1300.

    Article  CAS  PubMed  Google Scholar 

  26. The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Article  PubMed Central  Google Scholar 

  27. Verhaak RGW, Wouters BJ, Erpelinck CAJ, Abbas S, Beverloo HB, Lugthart S et al. Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica 2009; 94: 131–134.

    Article  PubMed  Google Scholar 

  28. Baldus CD, Bullinger L . Gene expression with prognostic implications in cytogenetically normal acute myeloid leukemia. Semin Oncol 2008; 35: 356–364.

    Article  CAS  PubMed  Google Scholar 

  29. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  30. Foran JM . New prognostic markers in acute myeloid leukemia: perspective from the clinic. Hematology Am Soc Hematol Educ Program 2010; 2010: 47–55.

    Article  PubMed  Google Scholar 

  31. Bago R, Malik N, Munson MJ, Prescott A, Davies P, Sommer EM et al. Characterisation of VPS34-IN1, a selective inhibitor of Vps34 reveals that the phosphatidylinositol 3-phosphate binding SGK3 protein kinase is a downstream target of class III PI-3 kinase. Biochem J 2014; 463: 413–427.

    Article  CAS  PubMed  Google Scholar 

  32. Gasser JA, Inuzuka H, Lau AW, Wei W, Beroukhim R, Toker A . SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Mol Cell 2014; 56: 595–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr John Dick and Dr Norman Iscove for critical reagents and invaluable advice, and Dr Pier Paolo Scaglioni, Dr Rob Laister and Dr Michael Jain for insightful discussions, Dr Joanne Kotsopoulos for statistical analysis, and Raffi Salmena for colony counting. Pi-Glo: Universal Bioluminescent Phosphatase Assay system was a kind gift from Promega. LS is funded in part by a Human Frontier Career Development Award (CDA-00079/2011). This work was supported in part by a Leukemia and Lymphoma Society of Canada Grant (317359/2013) to LS.

Author information

Author notes

  1. R He, J F Woolley and M H Son: These authors contributed equally to this work.

Authors and Affiliations

  1. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    I Dzneladze, R He, J F Woolley, M H Son, M H Sharobim, S A Greenberg, M Gabra, C Langlois, A Rashid, A Hakem, N Ibrahimova, A Arruda, M D Minden & L Salmena

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    I Dzneladze, A Rashid, M D Minden & L Salmena

  3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    J F Woolley, M H Son, M H Sharobim, M Gabra & L Salmena

  4. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    S A Greenberg & M D Minden

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

    B Löwenberg & P J M Valk

Authors
  1. I Dzneladze
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J F Woolley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M H Son
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M H Sharobim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S A Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Gabra
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Langlois
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Rashid
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Hakem
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N Ibrahimova
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Arruda
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. B Löwenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P J M Valk
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M D Minden
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. L Salmena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Salmena.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dzneladze, I., He, R., Woolley, J. et al. INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia. Leukemia 29, 1485–1495 (2015). https://doi.org/10.1038/leu.2015.51

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.51

This article is cited by

Search

Advanced search

Quick links