Concise Review | Published:

Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications

Leukemia volume 29, pages 269278 (2015) | Download Citation

Abstract

Acute myeloid leukemia (AML) carrying nucleophosmin (NPM1) mutations displays distinct biological and clinical features that led to its inclusion as a provisional disease entity in the 2008 World Health Organization (WHO) classification of myeloid neoplasms. Studies of the molecular mechanisms underlying the pathogenesis of NPM1-mutated AML have benefited greatly from several mouse models of this leukemia developed over the past few years. Immunocompromised mice xenografted with NPM1-mutated AML served as the first valuable tool for defining the biology of the disease in vivo. Subsequently, genetically engineered mouse models of the NPM1 mutation, including transgenic and knock-in alleles, allowed the generation of mice with a constant genotype and a reproducible phenotype. These models have been critical for investigating the nature of the molecular effects of these mutations, defining the function of leukemic stem cells in NPM1-mutated AML, identifying chemoresistant preleukemic hemopoietic stem cells and unraveling the key molecular events that cooperate with NPM1 mutations to induce AML in vivo. Moreover, they can serve as a platform for the discovery and validation of new antileukemic drugs in vivo. Advances derived from the analysis of these mouse models promise to greatly accelerate the development of new molecularly targeted therapies for patients with NPM1-mutated AML.

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References

  1. 1.

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

  2. 2.

    , , , , , et al. Mutational landscape and significance across 12 major cancer types. Nature 2013; 502333–339.

  3. 3.

    , , , , , et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352254–266.

  4. 4.

    , , , . Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 2007; 109874–885.

  5. 5.

    , , , , , et al. Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? Blood 2011; 117: 1109–1120.

  6. 6.

    , , , , , et al. Cytoplasmic mutated nucleophosmin is stable in primary leukemic cells and in a xenotransplant model of NPMc+ acute myeloid leukemia in SCID mice. Haematologica 2008; 93: 775–779.

  7. 7.

    , , , , , . Late relapse of acute myeloid leukemia with mutated NPM1 after eight years: evidence of NPM1 mutation stability. Haematologica 2009; 94: 298–300.

  8. 8.

    , , , , , et al. In human genome, generation of a nuclear export signal through duplication appears unique to nucleophosmin (NPM1) mutations and is restricted to AML. Leukemia 2008; 22: 1285–1289.

  9. 9.

    , , , , , et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 2014; 28: 78–87.

  10. 10.

    , , , , , et al. The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. Genes Chromosomes Cancer 2013; 52: 410–422.

  11. 11.

    , , , , , et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360: 765–773.

  12. 12.

    , , , , , et al. NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia. Haematologica 2008; 93: 439–442.

  13. 13.

    , , , , , et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood 2005; 106: 899–902.

  14. 14.

    , , , , , et al. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci USA 2008; 105: 3945–3950.

  15. 15.

    , , , , , et al. AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features. Blood 2009; 114: 3024–3032.

  16. 16.

    , , , , , et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

  17. 17.

    , , , , , , , . Acute myeloid leukaemia with recurrent genetic abnormalities. WHO Classification of tumours of haematopoietic and lymphoid tissues. I.A.R.C. International Agency for Research on Cancer: Lyon, 2008. 110–123.

  18. 18.

    , , , , , et al. Cell line OCI/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin. Leukemia 2005; 19: 1760–1767.

  19. 19.

    , , , , , et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood 2006; 107: 4514–4523.

  20. 20.

    , , , , , et al. Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia 2009; 23: 1731–1743.

  21. 21.

    , , , , , et al. The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence. Oncogene 2007; 26: 7391–7400.

  22. 22.

    , , , , , et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.

  23. 23.

    , , , , , et al. CD34+ cells from AML with mutated NPM1 harbor cytoplasmic mutated nucleophosmin and generate leukemia in immunocompromised mice. Blood 2010; 116: 3907–3922.

  24. 24.

    , , , , , et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(−) fraction. Blood 2010; 115: 1976–1984.

  25. 25.

    , , , , , et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Tansl Med 2012; 4: 149ra18.

  26. 26.

    , , , , , et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506: 328–333.

  27. 27.

    , , , , . Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA 2014; 111: 2548–2553.

  28. 28.

    , , , , , et al. The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model. Blood 2010; 115: 3341–3345.

  29. 29.

    , , , , , et al. Expression of the cytoplasmic NPM1 mutant (NPMc+) causes the expansion of hematopoietic cells in zebrafish. Blood 2010; 115: 3329–3340.

  30. 30.

    , , , , , et al. A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF. Leukemia 2009; 23: 501–509.

  31. 31.

    , , , , , et al. Up-regulation of translation eukaryotic initiation factor 4E in nucleophosmin 1 haploinsufficient cells results in changes in CCAAT enhancer-binding protein alpha activity: implications in myelodysplastic syndrome and acute myeloid leukemia. J Biol Chem 2012; 287: 32728–32737.

  32. 32.

    , , , , , et al. Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 2008; 111: 3859–3862.

  33. 33.

    , , , , , et al. The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model. Blood 2013; 121: 3447–3458.

  34. 34.

    , , , , , et al. NPMc+ and FLT3_ITD mutations cooperate in inducing acute leukaemia in a novel mouse model. Leukemia 2013; 27: 2248–2251.

  35. 35.

    , , , , , et al. Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: Impact on WHO classification. Blood 2006; 108: 4146–4155.

  36. 36.

    , , , , , et al. Multilineage dysplasia has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1). Blood 2010; 115: 3776–3786.

  37. 37.

    , , , , , et al. MicroRNA fingerprints during human megakaryocytopoiesis. Proc Natl Acad Sci USA 2006; 103: 5078–5083.

  38. 38.

    , , , , , et al. Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice. Nat Genet 2011; 43: 470–475.

  39. 39.

    , , , , , et al. A knock-in Npm1 mutation in mice results in myeloproliferation and implies a perturbation in hematopoietic microenvironment. PloS one 2012; 7: e49769.

  40. 40.

    , , , , , et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest 2005; 115: 2159–2168.

  41. 41.

    , , , , , et al. KIT with D816 mutations cooperates with CBFB-MYH11 for leukemogenesis in mice. Blood 2012; 119: 1511–1521.

  42. 42.

    . Hematologic malignancies. Curr Opin Hematol 2001; 8: 189–191.

  43. 43.

    , , , , , . Myeloid malignancies: mutations, models and management. BMC cancer 2012; 12: 304.

  44. 44.

    , , , , . Mutational landscape of AML with normal cytogenetics: biological and clinical implications. Blood reviews 2013; 27: 13–22.

  45. 45.

    , , , , , et al. A powerful molecular synergy between mutant Nucleophosmin and Flt3-ITD drives acute myeloid leukemia in mice. Leukemia 2013; 27: 1917–1920.

  46. 46.

    , , , , , et al. NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease. Exp Hematol. 2013; 42: 101–113.

  47. 47.

    , , , , , et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 2001; 61: 7233–7239.

  48. 48.

    , , , , , et al. A study of the leukemogenic interaction between mutant NPM1 and NRASG12D in conditional knock-in mice. Haematologica 2013; 98((s1)):464, abstract S1126.

  49. 49.

    , , , . Nucleophosmin and cancer. Nat Rev Cancer 2006; 6: 493–505.

  50. 50.

    , , , , , et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature 2005; 437: 147–153.

  51. 51.

    , , , , , . Acute myeloid leukemia with mutated nucleophosmin (NPM1): any hope for a targeted therapy?. Blood Rev. 2011; 25: 247–254.

  52. 52.

    , , , , , et al. Identification of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res. 2009; 69: 510–517.

  53. 53.

    , . NPM1-mutated AML: targeting by disassembling. Blood 2011; 118: 2936–2938.

  54. 54.

    , . Nucleolar targeting: the hub of the matter. EMBO Rep. 2009; 10: 231–238.

  55. 55.

    , . A study of correlation between NPM-translocation and apoptosis in cells induced by daunomycin. Biochem Pharmacol 1999; 57: 1265–1273.

  56. 56.

    , . Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J 2003; 22: 6068–6077.

  57. 57.

    , , , , , et al. Chemotherapeutic drugs inhibit ribosome biogenesis at various levels. J Biol Chem 2010; 285: 12416–12425.

  58. 58.

    , , , , , et al. Nucleophosmin mutations alter its nucleolar localization by impairing G-quadruplex binding at ribosomal DNA. Nucleic Acids Res 2013; 41: 3228–3239.

  59. 59.

    , , , , , et al. Detection of exon 12 type A mutation of NPM1 gene in IMS-M2 cell line. Leuk Res 2010; 34: 261–262.

  60. 60.

    , , , , , et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica 2009; 94: 54–60.

  61. 61.

    , , , , , et al. The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and CEBPA. Blood 2010; 115: 948–956.

  62. 62.

    , . Will FLT3 inhibitors fulfill their promise in acute meyloid leukemia?. Curr Opin Hematol 2014; 21: 72–78.

  63. 63.

    , , , , , et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia 2014; 28: 311–320.

  64. 64.

    , , , , , . Successful treatment of molecular relapse in NPM1-positive AML using 5-azacytidine. Leukemia 2010; 24: 236–237.

  65. 65.

    , , , , , et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 2013; 122: 2877–2887.

  66. 66.

    , , , , , et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013; 340: 622–626.

  67. 67.

    , , , , , et al. Leukemic stem cells of acute myeloid leukemia patients carrying NPM1 mutation are candidates for targeted immunotherapy. Leukemia 2014; 28: 1759–1762.

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Acknowledgements

This work was supported by the Associazione Italiana Ricerca Cancro (AIRC) (IG 2013 n.14595), the Associazione Umbra contro le Leucemie e i Linfomi (AULL) and Italian Minister of Health, Project ‘Ricerca Finalizzata 2008’ (Grant n. RF-UMB-2008-1198396). GV is funded by a Welcome Trust Senior Fellowship in Clinical Science. AM is funded by a Kay Kendall Leukaemia Fund project grant.

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Affiliations

  1. Institute of Hematology, University of Perugia, Perugia, Italy

    • P Sportoletti
    • , E Varasano
    • , R Rossi
    • , E Tiacci
    • , M P Martelli
    •  & B Falini
  2. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    • A Mupo
    •  & G Vassiliou

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Competing interests

B. Falini applied for a patent on the clinical use of NPM1 mutants. The remaining authors declare no conflict of interest.

Corresponding authors

Correspondence to P Sportoletti or B Falini.

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DOI

https://doi.org/10.1038/leu.2014.257

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