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:

Gene Expression Profiles and Microarrays

Gene expression profiling of acute promyelocytic leukaemia identifies two subtypes mainly associated with Flt3 mutational status

Leukemia volumeĀ 20,Ā pages 103ā€“114 (2006)Cite this article

Abstract

Acute promyelocytic leukaemia (APL) is a well-defined disease characterized by a typical morphology of leukaemic cells, the presence of t(15;17) translocation and the unique sensitivity to the differentiating effect of all-trans retinoic acid. Nevertheless, some aspects are variable among APL patients, with differences substantially related to morphological variants, peripheral leukocytes count, the presence of a disseminated intravascular coagulopathy, different PML/RARĪ± isoforms (long, variable or short) and Fms-like tyrosine kinase 3 (Flt3) mutations. In order to better define this variability, we investigated the gene expression profiles of 18 APL cases revealing, besides a high uniformity in gene expression pattern, the presence of few robust differences among patients able to identify, by an unsupervised analysis, two major clusters of patients characterized by different phenotypes (hypogranular M3v vs classical M3) and by the presence or absence of Flt3 internal tandem duplications (ITDs). Further supervised analysis confirmed that Flt3 status was the APL parameter best associated with these two subgroups. We identified, between Flt3 wild-type and Flt3-ITDs subsets, 147 differentially expressed genes that were involved in the cytoskeleton organization, in the cell adhesion and migration, in the proliferation and the coagulation/inflammation pathways as well as in differentiation and myeloid granules constitution suggesting a role of Flt3 mutations in the pathogenesis and clinical manifestations of APL.

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

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Melnick A, Licht JD . Deconstructing a disease: RARĪ±, its fusion partner, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167ā€“3215.

    CASĀ  PubMedĀ  Google ScholarĀ 

  2. 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: 1605ā€“1616.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  3. 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: 10008ā€“10013.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  4. 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: 299ā€“307.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  5. Jaffe ES, Harris NL, Stein H, Vardiman JW . World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Haematopoietic Tissues. IARC Press: Lyon, France, 2001.

    Google ScholarĀ 

  6. Brown D, Kogan S, Lagasse E, Weissman I, Alcalay M, Pelicci PG et al. A PMLRARalpha transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci USA 1997; 94: 2551ā€“2556.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  7. He LZ, Triboli C, Rivi R, Peruzzi D, Pelicci PG, Soares V et al. Acute leukemia with promyelocytic features in PML/RARalpha transgenic mice. Proc Natl Acad Sci USA 1997; 94: 5302ā€“5307.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  8. Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ . Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR alpha under control of cathepsin G regulatory sequences. Blood 1997; 89: 376ā€“387.

    CASĀ  PubMedĀ  Google ScholarĀ 

  9. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98: 1752ā€“1759.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  10. Thiede C, Strudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326ā€“4335.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  11. Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci USA 2002; 99: 8283ā€“8288.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  12. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59ā€“66.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  13. Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 2002; 16: 2185ā€“2189.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  14. Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M et al. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood 1996; 88: 1390ā€“1398.

    CASĀ  PubMedĀ  Google ScholarĀ 

  15. Borrow J, Goddard AD, Gibbons B, Katz F, Swirsky D, Fioretos T et al. Diagnosis of acute promyelocytic leukaemia by RT-PCR: detection of PML-RARA and RARA-PML fusion transcripts. Br J Haematol 1992; 82: 529ā€“540.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  16. Kiyoi H, Naoe T, Yokota S, Nakano M, Minami S, Kuriyama K, et al, and the Leukemia Study Group of Ministry of Health and Welfare (Kohseisho). Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia 1997; 11: 1447ā€“1452.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  17. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y . Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434ā€“2439.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  18. Hughes TR, Mao M, Jones AR, Burchard J, Marton MJ, Shannon KW et al. Expression profiling using microarrays fabricated by an ink-jet oligonucleotide synthesizer. Nat Biotechnol 2001; 19: 342ā€“347.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  19. Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95: 14863ā€“14868.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  20. Efron B, Tibshirani R . Empirical Bayes methods and false discovery rates for microarrays. Genet Epidemiol 2002; 23: 70ā€“86.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  21. Joliffe IT . Principal Component Analysis. Springer: New York, 1986.

    BookĀ  Google ScholarĀ 

  22. Shih LY, Kuo MC, Liang DC, Huang CF, Lin TL, Wu JH et al. Internal tandem duplication and Asp835 mutations of the FMS-like tyrosine kinase 3 (FLT3) gene in acute promyelocytic leukemia. Cancer 2003; 98: 1206ā€“1216.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  23. Au WY, Fung A, Chim CS, Lie AK, Liang R, Ma ES et al. FLT-3 aberrations in acute promyelocytic leukaemia: clinicopathological associations and prognostic impact. Br J Haematol 2004; 125: 463ā€“469.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  24. Simon R, Radmacher MD, Dobbin K, McShane LM . Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. J Natl Cancer Inst 2003; 95: 14ā€“18.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  25. Hamann J, Eichler W, Hamann D, Kerstens HM, Poddighe PJ, Hoovers JM et al. Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain. J Immunol 1995; 155: 1942ā€“1950.

    CASĀ  PubMedĀ  Google ScholarĀ 

  26. Black RA . Tumor necrosis factor-alpha converting enzyme. Int J Biochem Cell Biol 2002; 34: 1ā€“5.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  27. Smyth EM, FitzGerald GA . Human prostacyclin receptor. Vitam Horm 2002; 65: 149ā€“165.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  28. Zipfel PF, Jokiranta TS, Hellwage J, Koistinen V, Meri S . The factor H protein family. Immunopharmacology 1999; 42: 53ā€“60.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  29. Napoleone E, di Santo A, Peri G, Mantovani A, de Gaetano G, Donati MB et al. The long pentraxin PTX3 up-regulates tissue factor in activated monocytes: another link between inflammation and clotting activation. J Leukoc Biol 2004; 76: 203ā€“209.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  30. Lorant DE, Zimmerman GA, McIntyre TM, Prescott SM . Platelet-activating factor mediates procoagulant activity on the surface of endothelial cells by promoting leukocyte adhesion. Semin Cell Biol 1995; 6: 295ā€“303.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  31. Hayward CP . Multimerin: a bench-to-bedside chronology of a unique platelet and endothelial cell protein ā€“ from discovery to function to abnormalities in disease. Clin Invest Med 1997; 20: 176ā€“187.

    CASĀ  PubMedĀ  Google ScholarĀ 

  32. Liu FT, Rabinovich GA . Galectins as modulators of tumour progression. Nat Rev Cancer 2005; 5: 29ā€“41.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  33. Almkvist J, Karlsson A . Galectins as inflammatory mediators. Glycoconj J 2004; 19: 575ā€“581.

    ArticleĀ  Google ScholarĀ 

  34. Sherbet GV, Lakshmi MS . S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis. Anticancer Res 1998; 18: 2415ā€“2421.

    CASĀ  PubMedĀ  Google ScholarĀ 

  35. Rao KN . The significance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis. Anticancer Res 1995; 15: 309ā€“314.

    CASĀ  PubMedĀ  Google ScholarĀ 

  36. Cuthbert JA, Lipsky PE . Regulation of lymphocyte proliferation by cholesterol: the role of endogenous sterol metabolism and low density lipoprotein receptors. Int J Tissue React 1987; 9: 447ā€“457.

    CASĀ  PubMedĀ  Google ScholarĀ 

  37. Banker DE, Mayer SJ, Li HY, Willman CL, Appelbaum FR, Zager RA . Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells. Blood 2004; 104: 1816ā€“1824.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  38. Liu J, Bang AG, Kintner C, Orth AP, Chanda SK, Ding S et al. Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis. Proc Natl Acad Sci USA 2005; 102: 1927ā€“1932.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  39. Kawano Y, Kypta R . Secreted antagonists of the Wnt signalling pathway. J Cell Sci 2003; 116: 2627ā€“2634.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  40. Faurschou M, Borregaard N . Neutrophil granules and secretory vesicles in inflammation. Microbes Infect 2003; 5: 1317ā€“1327.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  41. Luce MJ, Burrows PD . The neuronal EGF-related genes NELL1 and NELL2 are expressed in hemopoietic cells and developmentally regulated in the B lineage. Gene 1999; 231: 121ā€“126.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  42. Veal E, Groisman R, Eisenstein M, Gill G . The secreted glycoprotein CREG enhances differentiation of NTERA-2 human embryonal carcinoma cells. Oncogene 2000; 19: 2120ā€“2128.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  43. Konopleva M, Elstner E, McQueen TJ, Tsao T, Sudarikov A, Hu W et al. Peroxisome proliferator-activated receptor gamma and retinoid Ɨ receptor ligands are potent inducers of differentiation and apoptosis in leukemias. Mol Cancer Ther 2004; 3: 1249ā€“1262.

    CASĀ  PubMedĀ  Google ScholarĀ 

  44. Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S et al. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc Natl Acad Sci USA 1998; 95: 11590ā€“11595.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  45. Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon C, Barbui T et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of thye GIMEMA and PETHEMA cooperative groups. Blood 2000; 96: 1247ā€“1253.

    CASĀ  PubMedĀ  Google ScholarĀ 

  46. Callens C, Chevret S, Cayuela JM, Cassinat B, Raffoux E, de Botton S et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 2005; 19: 1153ā€“1160.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  47. Haferlach T, Kohlmann A, Schnittger S, Dugas M, Hiddemann W, Kern W et al. AML M3 and AML M3 variant each have a distinct gene expression signature but also share patterns different from other genetically defined AML subtypes. Genes Chromosomes Cancer 2005; 43: 113ā€“127.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  48. Tse KF, Mukherjee G, Small D . Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia 2000; 14: 1766ā€“1776.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  49. Zheng R, Levis M, Piloto O, Brown P, Baldwin BR, Gorin NC et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 2004; 103: 267ā€“274.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  50. Levis M, Tse KF, Smith BD, Garrett E, Small D . A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood 2001; 98: 885ā€“887.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  51. Zheng R, Friedman AD, Small D . Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations. Blood 2002; 100: 4154ā€“4161.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  52. Zheng R, Friedman AD, Levis M, Li L, Weir EG, Small D . Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression. Blood 2004; 103: 1883ā€“1890.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  53. Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood 2003; 101: 3164ā€“3173.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  54. Kim KT, Baird K, Ahn JY, Meltzer P, Lilly M, Levis M et al. Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. Blood 2005; 105: 1759ā€“1767.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  55. Imai Y, Kurokawa M, Tanaka K, Friedman AD, Ogawa S, Mitani K et al. TLE, the human homolog of groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation. Biochem Biophys Res Commun 1998; 252: 582ā€“589.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  56. Javed A, Guo B, Hiebert S, Choi JY, Green J, Zhao SC et al. Groucho/TLE/R-esp proteins associate with the nuclear matrix and repress RUNX (CBF(alpha)/AML/PEBP2(alpha)) dependent activation of tissue-specific gene transcription. J Cell Sci 2000; 113: 2221ā€“2231.

    CASĀ  PubMedĀ  Google ScholarĀ 

  57. Michaud J, Scott HS, Escher R . AML1 interconnected pathways of leukemogenesis. Cancer Invest 2003; 21: 105ā€“136.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  58. Kurokawa M, Hirai H . Role of AML1/Runx1 in the pathogenesis of hematological malignancies. Cancer Sci 2003; 94: 841ā€“846.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  59. Planaguma J, Diaz-Fuertes M, Gil-Moreno A, Abal M, Monge M, Garcia A et al. A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma. Cancer Res 2004; 64: 8846ā€“8853.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  60. Polakis P . The oncogenic activation of beta-catenin. Curr Opin Genet Dev 1999; 9: 15ā€“21.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  61. Tickenbrock L, Schwable J, Wiedehage M, Steffen B, Sargin B, Choudhary C et al. Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood 2005; 105: 3699ā€“3706.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

Download references

Acknowledgements

This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy; Associazione Italiana contro le Leucemie (AIL), Modena, Italy; Cassa di Risparmio of Modena Foundation, Modena, Italy.

Author information

Author notes

  1. R Marasca and R Maffei: Both authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy

    R Marasca,Ā R Maffei,Ā P Zucchini,Ā I Castelli,Ā A Saviola,Ā S Martinelli,Ā A Ferrari,Ā M Fontana,Ā S RavanettiĀ &Ā G Torelli

Authors
  1. R Marasca
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  2. R Maffei
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  3. P Zucchini
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  4. I Castelli
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  5. A Saviola
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  6. S Martinelli
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  7. A Ferrari
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  8. M Fontana
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  9. S Ravanetti
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  10. G Torelli
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

Corresponding author

Correspondence to R Marasca.

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

Marasca, R., Maffei, R., Zucchini, P. et al. Gene expression profiling of acute promyelocytic leukaemia identifies two subtypes mainly associated with Flt3 mutational status. Leukemia 20, 103ā€“114 (2006). https://doi.org/10.1038/sj.leu.2404000

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404000

Keywords

This article is cited by

Search

Advanced search

Quick links