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:

Molecular Targets for Therapy

Identification of a molecular signature predictive of sensitivity to differentiation induction in acute myeloid leukemia

Leukemia volume 20, pages 1751–1758 (2006)Cite this article

Abstract

Acute myeloid leukemia (AML) blasts are immature committed myeloid cells unable to spontaneously undergo terminal maturation, and characterized by heterogeneous sensitivity to natural differentiation inducers. Here, we show a molecular signature predicting the resistance or sensitivity of six myeloid cell lines to differentiation induced in vitro with retinoic acid or vitamin D. The identified signature was further validated by TaqMan assay for the prediction of response to an in vitro differentiation assay performed on 28 freshly isolated AML blast populations. The TaqMan assay successfully predicts the in vitro resistance or responsiveness of AML blasts to differentiation inducers. Furthermore, performing a meta-analysis of publicly available microarray data sets, we also show the accuracy of our prediction on known phenotypes and suggest that our signature could become useful for the identification of patients eligible for new therapeutic strategies.

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

Similar content being viewed by others

References

  1. Tallman MS . Acute promyelocytic leukemia as a paradigm for targeted therapy. Semin Hematol 2004; 41 (Suppl 4): 27–32.

    Article  CAS  PubMed  Google Scholar 

  2. Manfredini R, Trevisan F, Grande A, Tagliafico E, Montanari M, Lemoli R et al. Induction of a functional vitamin D receptor in all-trans-retinoic acid-induced monocytic differentiation of M2-type leukemic blast cells. Cancer Res 1999; 59: 3803–3811.

    CAS  PubMed  Google Scholar 

  3. Kumagai T, Shih LY, Hughes SV, Desmond JC, O’Kelly J, Hewison M et al. 19-Nor-1,25(OH)2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia. Cancer Res 2005; 65: 2488–2497.

    Article  CAS  PubMed  Google Scholar 

  4. Waxman S . Differentiation therapy in acute myelogenous leukemia (non-APL). Leukemia 2000; 14: 491–496.

    Article  CAS  PubMed  Google Scholar 

  5. Bruserud O, Gjertsen BT . New strategies for the treatment of acute myelogenous leukemia: differentiation induction – present use and future possibilities. Stem Cells 2000; 18: 157–165.

    Article  CAS  PubMed  Google Scholar 

  6. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999; 286: 531–537.

    Article  CAS  PubMed  Google Scholar 

  7. Schoch C, Kohlmann A, Schnittger S, Brors B, Dugas M, Mergenthaler S et al. Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc Natl Acad Sci USA 2002; 99: 10008–10013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kohlmann A, Schoch C, Schnittger S, Dugas M, Hiddemann W, Kern W et al. Molecular characterization of acute leukemias by use of microarray technology. Genes Chromosomes Cancer 2003; 37: 396–405.

    Article  CAS  PubMed  Google Scholar 

  9. Debernardi S, Lillington DM, Chaplin T, Tomlinson S, Amess J, Rohatiner A et al. Genome-wide analysis of acute myeloid leukemia with normal karyotype reveals a unique pattern of homeobox gene expression distinct from those with translocation-mediated fusion events. Genes Chromosomes Cancer 2003; 37: 149–158.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Bullinger L, Dohner K, Bair E, Frohling S, Schlenk RF, Tibshirani R et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 2004; 350: 1605–1616.

    Article  CAS  PubMed  Google Scholar 

  12. Haferlach T, Kern W, Schoch C, Schnittger S, Sauerland MC, Heinecke A et al. A new prognostic score for patients with acute myeloid leukemia based on cytogenetics and early blast clearance in trials of the German AML Cooperative Group. Haematologica 2004; 89: 408–418.

    PubMed  Google Scholar 

  13. Kohlmann A, Schoch C, Dugas M, Schnittger S, Hiddemann W, Kern W et al. New insights into MLL gene rearranged acute leukemias using gene expression profiling: shared pathways, lineage commitment, and partner genes. Leukemia 2005; 19: 953–964.

    Article  CAS  PubMed  Google Scholar 

  14. Kohlmann A, Schoch C, Dugas M, Rauhut S, Weninger F, Schnittger S et al. Pattern robustness of diagnostic gene expression signatures in leukemia. Genes Chromosomes Cancer 2005; 42: 299–307.

    Article  CAS  PubMed  Google Scholar 

  15. Haferlach T, Kohlmann A, Schnittger S, Dugas M, Hiddemann W, Kern W et al. Global approach to the diagnosis of leukemia using gene expression profiling. Blood 2005; 106: 1189–1198.

    Article  CAS  PubMed  Google Scholar 

  16. Heuser M, Wingen LU, Steinemann D, Cario G, von Neuhoff N, Tauscher M et al. Gene-expression profiles and their association with drug resistance in adult acute myeloid leukemia. Haematologica 2005; 90: 1484–1492.

    CAS  PubMed  Google Scholar 

  17. Koeffler HP, Golde DW . Acute myelogenous leukemia: a human cell line responsive to colony-stimulating activity. Science 1978; 200: 1153–1154.

    Article  CAS  PubMed  Google Scholar 

  18. Furley AJ, Reeves BR, Mizutani S, Altass LJ, Watt SM, Jacob MC et al. Divergent molecular phenotypes of KG1 and KG1a myeloid cell lines. Blood 1986; 68: 1101–1107.

    CAS  PubMed  Google Scholar 

  19. Asou H, Tashiro S, Hamamoto K, Otsuji A, Kita K, Kamada N . Establishment of a human acute myeloid leukemia cell line (Kasumi-1) with 8;21 chromosome translocation. Blood 1991; 77: 2031–2036.

    CAS  PubMed  Google Scholar 

  20. Tsuchiya S, Yamabe M, Yamaguchi Y, Kobayashi Y, Konno T, Tada K . Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer 1980; 26: 171–176.

    Article  CAS  PubMed  Google Scholar 

  21. Lanotte M, Martin Thouvenin V, Najman S, Balerini P, Valensi F, Berger R . NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). Blood 1991; 77: 1080–1086.

    CAS  PubMed  Google Scholar 

  22. James SY, Williams MA, Newland AC, Colston KW . Leukemia cell differentiation: cellular and molecular interactions of retinoids and vitamin D. Gen Pharmacol 1999; 32: 143–154.

    Article  CAS  PubMed  Google Scholar 

  23. Lea MA . Action of exogenous differentiating agents on gene expression in cancer cells. Crit Rev Oncol Hematol 1992; 13: 189–214.

    Article  CAS  PubMed  Google Scholar 

  24. Tagliafico E, Siena M, Zanocco-Marani T, Manfredini R, Tenedini E, Montanari M et al. Requirement of the coiled-coil domains of p92(c-Fes) for nuclear localization in myeloid cells upon induction of differentiation. Oncogene 2003; 22: 1712–1723.

    Article  CAS  PubMed  Google Scholar 

  25. Grande A, Montanari M, Tagliafico E, Manfredini R, Marani TZ, Siena M et al. Physiological levels of 1alpha, 25 dihydroxyvitamin D3 induce the monocytic commitment of CD34+ hematopoietic progenitors. J Leukocyte Biol 2002; 71: 641–651.

    CAS  PubMed  Google Scholar 

  26. Manfredini R, Zini R, Salati S, Siena M, Tenedini E, Tagliafico E et al. The kinetic status of hematopoietic stem cell subpopulations underlies a differential expression of genes involved in self-renewal, commitment, and engraftment. Stem Cells 2005; 23: 496–506.

    Article  CAS  PubMed  Google Scholar 

  27. Montanari M, Gemelli C, Tenedini E, Zanocco MT, Vignudelli T, Siena M et al. Correlation between differentiation plasticity and mRNA expression profiling of CD34+ derived. Cell Death Differ 2005; 12: 1588–1600.

    Article  CAS  PubMed  Google Scholar 

  28. Tagliafico E, Tenedini E, Bergamaschi A, Manfredini R, Percudani R, Siena M et al. Gene expression profile of Vitamin D3 treated HL60 cells shows an incomplete molecular phenotypic conversion to monocytes. Cell Death Differ 2002; 9: 1185–1195.

    Article  CAS  PubMed  Google Scholar 

  29. Ferrari S, Donelli A, Manfredini R, Sarti M, Roncaglia R, Tagliafico E et al. Differential effects of c-myb and c-fes antisense oligodeoxynucleotides on granulocytic differentiation of human myeloid leukemia HL60 cells. Cell Growth Differ 1990; 1: 543–548.

    CAS  PubMed  Google Scholar 

  30. Grande A, Montanari M, Manfredini R, Tagliafico E, Zanocco-Marani T, Trevisan F et al. A functionally active RARalpha nuclear receptor is expressed in retinoic acid non responsive early myeloblastic cell lines. Cell Death Differ 2001; 8: 70–82.

    Article  CAS  PubMed  Google Scholar 

  31. Grande A, Manfredini R, Tagliafico E, Balestri R, Pizzanelli M, Papa S et al. All trans retinoic acid induces simultaneously granulocytic differentiation and expression of inflammatory cytokines in HL 60 cells. Exp Hematol 1995; 23: 117–125.

    CAS  PubMed  Google Scholar 

  32. Liu WM, Mei R, Di X, Ryder TB, Hubbell E, Dee S et al. Analysis of high density expression microarrays with signed-rank call algorithms. Bioinformatics 2002; 18: 1593–1599.

    Article  CAS  PubMed  Google Scholar 

  33. 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: 249–264.

    Article  PubMed  Google Scholar 

  34. Li C, Wong WH . Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA 2001; 98: 31–36.

    Article  CAS  PubMed  Google Scholar 

  35. Li C, Hung WW . Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application. Genome Biol 2001; 2: 1–11.

    Google Scholar 

  36. Manfredini R, Grande A, Tagliafico E, Barbieri D, Zucchini P, Citro G et al. Inhibition of c-fes expression by an antisense oligomer causes apoptosis of HL60 cells induced to granulocytic differentiation. J Exp Med 1993; 178: 381–389.

    Article  CAS  PubMed  Google Scholar 

  37. Tsiftsoglou AS, Pappas IS, Vizirianakis IS . Mechanisms involved in the induced differentiation of leukemia cells. Pharmacol Ther 2003; 100: 257–290.

    Article  CAS  PubMed  Google Scholar 

  38. Waxman S . Differentiation therapy in acute myelogenous leukemia (non-APL). Leukemia 2000; 14: 491–496.

    Article  CAS  PubMed  Google Scholar 

  39. Olsson I, Bergh G, Ehinger M, Gullberg U . Cell differentiation in acute myeloid leukemia. Eur J Haematol 1996; 57: 1–16.

    Article  CAS  PubMed  Google Scholar 

  40. Calvo KR, Knoepfler PS, Sykes DB, Pasillas MP, Kamps MP . Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia. Proc Natl Acad Sci USA 2001; 98: 13120–13125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Thorsteinsdottir U, Kroon E, Jerome L, Blasi F, Sauvageau G . Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia. Mol Cell Biol 2001; 21: 224–234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee BC, Cheng T, Adams GB, Attar EC, Miura N, Lee SB et al. P2Y-like receptor, GPR105 (P2Y14), identifies and mediates chemotaxis of bone-marrow hematopoietic stem cells. Genes Dev 2003; 17: 1592–1604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Donato JL, Ko J, Kutok JL, Cheng T, Shirakawa T, Mao XQ et al. Human HTm4 is a hematopoietic cell cycle regulator. J Clin Invest 2002; 109: 51–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med 2004; 350: 1828–1837.

    Article  CAS  PubMed  Google Scholar 

  45. Li W, Kessler P, Yeger H, Alami J, Reeve AE, Heathcott R et al. A gene expression signature for relapse of primary wilms tumors. Cancer Res 2005; 65: 2592–2601.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by AIL (Italian Association against Leukemia), AIRC (Italian Association for Cancer Research), CIB (Italian Consortium for Biotechnology) and MIUR. Tenedini Gemelli and Bianchi have fellowships of PRITT (Integrated Regional Programme for Innovation and Technology Transfer/ERGENTECH).

Author information

Authors and Affiliations

  1. Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Università di Modena e Reggio Emilia, Modena, Italy

    E Tagliafico, E Tenedini, R Manfredini, A Grande, F Ferrari, E Roncaglia, R Zini, S Salati, E Bianchi, C Gemelli, M Montanari, T Vignudelli, T Zanocco-Marani, S Parenti, U Torelli & S Ferrari

  2. Dipartimento di Processi Chimici dell'Ingegneria, Università di Padova, Padova, Italy

    S Bicciato

  3. Dipartimento Materno Infantile, Sezione di Oncoematologia Pediatrica, Università di Modena e Reggio Emilia, Modena, Italy

    P Paolucci

  4. Istituto di Ematologia ed Oncologia Medica ‘L. e A. Seragnoli’, Università di Bologna, Bologna, Italy

    G Martinelli, P P Piccaluga & M Baccarani

  5. Dipartimento di Scienze Mediche e del Lavoro, Università di Foggia, Ematologia, Foggia, Italy

    G Specchia

Authors
  1. E Tagliafico
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Tenedini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Manfredini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Grande
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Roncaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Bicciato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R Zini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Salati
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E Bianchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C Gemelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Montanari
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T Vignudelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T Zanocco-Marani
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. S Parenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. P Paolucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. G Martinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. P P Piccaluga
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M Baccarani
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. G Specchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. U Torelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. S Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Ferrari.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tagliafico, E., Tenedini, E., Manfredini, R. et al. Identification of a molecular signature predictive of sensitivity to differentiation induction in acute myeloid leukemia. Leukemia 20, 1751–1758 (2006). https://doi.org/10.1038/sj.leu.2404358

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404358

Keywords

This article is cited by

Search

Advanced search

Quick links