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Genomics, Gene Therapy And Proteomics

Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias

Abstract

Somatic mutations in nucleophosmin (NPM1) occur in approximately 35% of adult acute myeloid leukemia (AML). To assess the frequency of NPM1 mutations in pediatric AML, we sequenced NPM1 in the diagnostic blasts from 93 pediatric AML patients. Six cases harbored NPM1 mutations, with each case lacking common cytogenetic abnormalities. To explore the phenotype of the AMLs with NPM1 mutations, gene expression profiles were obtained using Affymetrix U133A microarrays. NPM1 mutations were associated with increased expression of multiple homeobox genes including HOXA9, A10, B2, B6 and MEIS1. As dysregulated homeobox gene expression is also a feature of MLL-rearranged leukemia, the gene expression signatures of NPM1-mutated and MLL-rearranged leukemias were compared. Significant differences were identified between these leukemia subtypes including the expression of different HOX genes, with NPM1-mutated AML showing higher levels of expression of HOXB2, B3, B6 and D4. These results confirm recent reports of perturbed HOX expression in NPM1-mutated adult AML, and provide the first evidence that the NPM1-mutated signature is distinct from MLL-rearranged AML. These findings suggest that mutated NPM1 leads to dysregulated HOX expression via a different mechanism than MLL rearrangement.

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References

  1. Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik MV, Steuber CP et al. Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood 1999; 94: 3707–3716.

    CAS  Google Scholar 

  2. Meshinchi S, Stirewalt DL, Alonzo TA, Zhang Q, Sweetser DA, Woods WG et al. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 2003; 102: 1474–1479.

    Article  CAS  Google Scholar 

  3. Beghini A, Ripamonti CB, Cairoli R, Cazzaniga G, Colapietro P, Elice F et al. KIT activating mutations: incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication. Haematologica 2004; 89: 920–925.

    CAS  Google Scholar 

  4. Goemans BF, Zwaan CM, Miller M, Zimmermann M, Harlow A, Meshinchi S et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia 2005; 19: 1536–1542.

    Article  CAS  Google Scholar 

  5. Kang HJ, Hong SH, Kim IH, Park BK, Han KS, Cho HI et al. Prognostic significance of FLT3 mutations in pediatric non-promyelocytic acute myeloid leukemia. Leuk Res 2005; 29: 617–623.

    Article  CAS  Google Scholar 

  6. Liang DC, Shih LY, Huang CF, Hung IJ, Yang CP, Liu HC et al. CEBPalpha mutations in childhood acute myeloid leukemia. Leukemia 2005; 19: 410–414.

    Article  CAS  Google Scholar 

  7. Dohner K, Tobis K, Ulrich R, Frohling S, Benner A, Schlenk RF et al. Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol 2002; 20: 3254–3261.

    Article  Google Scholar 

  8. Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T et al. Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia 2000; 14: 796–804.

    Article  CAS  Google Scholar 

  9. Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005; 106: 3618–3620.

    Article  CAS  Google Scholar 

  10. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics – interaction with other gene mutations. Blood 2005; 106: 3740–3746.

    Article  Google Scholar 

  11. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–266.

    Article  CAS  Google Scholar 

  12. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF et al. Nucleophosmin gene mutations are predictors of favourable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005; 106: 3733–3739.

    Article  CAS  Google Scholar 

  13. Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W et al. Mutations in nucleophosmin NPM1 in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 2005; 106: 3747–3754.

    Article  CAS  Google Scholar 

  14. Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood 2005; 106: 2854–2861.

    Article  CAS  Google Scholar 

  15. Borer RA, Lehner CF, Eppenberger HM, Nigg EA . Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell 1989; 56: 379–390.

    Article  CAS  Google Scholar 

  16. Cordell JL, Pulford KA, Bigerna B, Roncador G, Banham A, Colombo E et al. Detection of normal and chimeric nucleophosmin in human cells. Blood 1999; 93: 632–642.

    CAS  Google Scholar 

  17. Brady SN, Yu Y, Maggi Jr LB, Weber JD . ARF impedes NPM/B23 shuttling in an Mdm2-sensitive tumor suppressor pathway. Mol Cell Biol 2004; 24: 9327–9338.

    Article  CAS  Google Scholar 

  18. Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG . Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol 2002; 4: 529–533.

    Article  CAS  Google Scholar 

  19. Morris SW, Kirstein MN, Valentine MB, Dittmer K, Shapiro DN, Look AT et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1995; 267: 316–317.

    Article  CAS  Google Scholar 

  20. Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ . The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996; 87: 882–886.

    CAS  Google Scholar 

  21. Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB, Raimondi SC, Cohen KJ et al. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 1996; 12: 265–275.

    CAS  Google Scholar 

  22. Bischof D, Pulford K, Mason DY, Morris SW . Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Mol Cell Biol 1997; 17: 2312–2325.

    Article  CAS  Google Scholar 

  23. Falini B, Bolli N, Shan J, Martelli MP, Liso A, Pucciarini A 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.

    Article  CAS  Google Scholar 

  24. Falini B, Martelli MP, Bolli N, Bonasso R, Ghia E, Pallotta MT et al. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood 2006; 108: 1999–2005.

    Article  CAS  Google Scholar 

  25. Cazzaniga G, Dell’Oro MG, Mecucci C, Giarin E, Masetti R, Rossi V et al. Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood 2005; 106: 1419–1422.

    Article  CAS  Google Scholar 

  26. Grisendi S, Pandolfi PP . NPM mutations in acute myelogenous leukemia. N Engl J Med 2005; 352: 291–292.

    Article  CAS  Google Scholar 

  27. den Besten W, Kuo ML, Williams RT, Sherr CJ . Myeloid Leukemia-Associated Nucleophosmin Mutants Perturb p53-Dependent and Independent Activities of the Arf Tumor Suppressor Protein. Cell Cycle 2005; 4: 1–6.

    Google Scholar 

  28. Ross ME, Mahfouz R, Onciu M, Liu HC, Zhou X, Song G et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood 2004; 104: 3679–3687.

    Article  CAS  Google Scholar 

  29. 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  Google Scholar 

  30. Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 2002; 1: 133–143.

    Article  CAS  Google Scholar 

  31. Alcalay M, Tiacci E, Bergomas R, Bigerna B, Venturini E, Minardi SP 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.

    Article  CAS  Google Scholar 

  32. Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002; 30: 41–47.

    Article  CAS  Google Scholar 

  33. Ribeiro RC, Razzouk BI, Pounds S, Hijiya N, Pui CH, Rubnitz JE . Successive clinical trials for childhood acute myeloid leukemia at St Jude Children's Research Hospital, from 1980 to 2000. Leukemia 2005; 19: 2125–2129.

    Article  CAS  Google Scholar 

  34. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103: 620–625.

    Article  CAS  Google Scholar 

  35. Storey JD . A direct approach to false discovery rates. J R Stat Soc Ser B 2002; 64: 479–498.

    Article  Google Scholar 

  36. Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    Article  CAS  Google Scholar 

  37. Kaplen EL, Meier P . Nonparametric Estimation from Incomplete Observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  38. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer 1977; 35: 1–39.

    Article  CAS  Google Scholar 

  39. Nakagawa M, Kameoka Y, Suzuki R . Nucleophosmin in acute myelogenous leukemia. N Engl J Med 2005; 352: 1819–1820.

    CAS  Google Scholar 

  40. Eklund EA . The role of HOX genes in myeloid leukemogenesis. Curr Opin Hematol 2006; 13: 67–73.

    Article  CAS  Google Scholar 

  41. Abramovich C, Humphries RK . Hox regulation of normal and leukemic hematopoietic stem cells. Curr Opin Hematol 2005; 12: 210–216.

    Article  CAS  Google Scholar 

  42. Kawagoe H, Humphries RK, Blair A, Sutherland HJ, Hogge DE . Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia 1999; 13: 687–698.

    Article  CAS  Google Scholar 

  43. Roche J, Zeng C, Baron A, Gadgil S, Gemmill RM, Tigaud I et al. Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics. Leukemia 2004; 18: 1059–1063.

    Article  CAS  Google Scholar 

  44. Ferrando AA, Armstrong SA, Neuberg DS, Sallan SE, Silverman LB, Korsmeyer SJ et al. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood 2003; 102: 262–268.

    Article  CAS  Google Scholar 

  45. Sauvageau G, Thorsteinsdottir U, Hough MR, Hugo P, Lawrence HJ, Largman C et al. Overexpression of HOXB3 in hematopoietic cells causes defective lymphoid development and progressive myeloproliferation. Immunity 1997; 6: 13–22.

    Article  CAS  Google Scholar 

  46. Thorsteinsdottir U, Sauvageau G, Hough MR, Dragowska W, Lansdorp PM, Lawrence HJ et al. Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia. Mol Cell Biol 1997; 17: 495–505.

    Article  CAS  Google Scholar 

  47. Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G . Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J 1998; 17: 3714–3725.

    Article  CAS  Google Scholar 

  48. 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  Google Scholar 

  49. Fischbach NA, Rozenfeld S, Shen W, Fong S, Chrobak D, Ginzinger D et al. HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo. Blood 2005; 105: 1456–1466.

    Article  CAS  Google Scholar 

  50. Giampaolo A, Felli N, Diverio D, Morsilli O, Samoggia P, Breccia M et al. Expression pattern of HOXB6 homeobox gene in myelomonocytic differentiation and acute myeloid leukemia. Leukemia 2002; 16: 1293–1301.

    Article  CAS  Google Scholar 

  51. Pasqualucci L, Liso A, Martelli MP, Bolli N, Pacini R, Tabarrini A et al. Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: Impact on WHO classification. Blood 2006; 108: 4146–4155.

    Article  CAS  Google Scholar 

  52. Sauvageau G, Thorsteinsdottir U, Eaves CJ, Lawrence HJ, Largman C, Lansdorp PM et al. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev 1995; 9: 1753–1765.

    Article  CAS  Google Scholar 

  53. Antonchuk J, Sauvageau G, Humphries RK . HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell 2002; 109: 39–45.

    Article  CAS  Google Scholar 

  54. Grisendi S, Mecucci C, Falini B, Pandolfi PP . Nucleophosmin and cancer. Nat Rev Cancer 2006; 6: 493–505.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Stanley Pounds for statistical analyses and Zhongling Cai for technical assistance. This work was supported in part by National Cancer Institute grants P01 CA71907-10 (JRD), CA-21765 (Cancer Center CORE grant to St Jude Children's Research Hospital) by the American Lebanese and Syrian Associated Charities of St Jude Children's Research Hospital. CGM is supported by a St Jude Children's Research Hospital Physician Scientist Fellowship, a National Health and Medical Research Council (Australia) CJ Martin Fellowship, a Haematology Society of Australia and New Zealand/AMGEN Traveling Fellowship and a Royal College of Physicians of Australasia/CSL Fellowship.

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Mullighan, C., Kennedy, A., Zhou, X. et al. Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. Leukemia 21, 2000–2009 (2007). https://doi.org/10.1038/sj.leu.2404808

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