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Biological and clinical consequences of NPM1 mutations in AML

Leukemia volume 31, pages 798–807 (2017)Cite this article

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Abstract

Acute myeloid leukemia (AML) is characterized by accumulation of myeloid cells in the bone marrow because of impaired differentiation and proliferation, resulting in hematopoietic insufficiency. NPM1 is one of the most commonly mutated genes in AML, present in 20–30% of cases. Mutations in NPM1 represent a distinct entity in the World Health Organization (WHO) classification and commonly indicate a better risk prognosis. In this review, we discuss the many functions of NPM1, the consequence of mutations in NPM1 and possible mechanisms through which mutations lead to leukemogenesis. We also discuss clinical consequences of mutations, associated gene expression patterns and the role of NPM1 mutations in informing prognosis and therapeutic decisions and predicting relapse in AML.

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References

  1. 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  PubMed  Google Scholar 

  2. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et alThe 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemiaBlood 2016; 127: 2391–2405.

    Article  CAS  PubMed  Google Scholar 

  3. Federici L, Falini B . Nucleophosmin mutations in acute myeloid leukemia: a tale of protein unfolding and mislocalization. Protein Sci 2013; 22: 545–556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang W, Budhu A, Forgues M, Wang XW . Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication. Nat Cell Biol 2005; 7: 823–830.

    Article  CAS  PubMed  Google Scholar 

  5. Yu Jr Y, Maggi LB, Brady SN, Apicelli J, Dai M, Lu H et al. Nucleophosmin is essential for ribosomal protein L5 nuclear export. Mol Cell Biol 2006; 26: 3798–3809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bolli N, De Marco MF, Martelli MP, Bigerna B, Pucciarini A, Rossi R et al. A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF. Leukemia 2009; 23: 501–509.

    Article  CAS  PubMed  Google Scholar 

  7. Jian Y, Gao Z, Sun J, Shen Q, Feng F, Jing Y et al. RNA aptamers interfering with nucleophosmin oligomerization induce apoptosis of cancer cells. Oncogene 2009; 28: 4201–4211.

    Article  CAS  PubMed  Google Scholar 

  8. Chan WY, Liu QR, Borjigin J, Busch H, Rennert OM, Tease LA et al. Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth. Biochemistry 1989; 28: 1033–1039.

    Article  CAS  PubMed  Google Scholar 

  9. Hingorani K, Szebeni A, Olson MO . Mapping the functional domains of nucleolar protein B23. J Biol Chem 2000; 275: 24451–24457.

    Article  CAS  PubMed  Google Scholar 

  10. Nishimura Y, Ohkubo T, Furuichi Y, Umekawa H . Tryptophans 286 and 288 in the C-terminal region of protein B23.1 are important for its nucleolar localization. Biosci Biotechnol Biochem 2002; 66: 2239–2242.

    Article  CAS  PubMed  Google Scholar 

  11. Mitrea DM, Grace CR, Buljan M, Yun M-K, Pytel NJ, Satumba J et al. Structural polymorphism in the N-terminal oligomerization domain of NPM1. Proc Natl Acad Sci USA 2014; 111: 4466–4471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan P-K et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 2000; 103: 127–140.

    Article  CAS  PubMed  Google Scholar 

  13. Okuwaki M . The structure and functions of NPM1/Nucleophsmin/B23, a multifunctional nucleolar acidic protein. J Biochem 2008; 143: 441–448.

    Article  CAS  PubMed  Google Scholar 

  14. Okuwaki M, Tsujimoto M, Nagata K . The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23, is modulated by phosphorylation with a cell cycle-dependent kinase and by association with its subtype. Mol Biol Cell 2002; 13: 2016–2030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shandilya J, Swaminathan V, Gadad SS, Choudhari R, Kodaganur GS, Kundu TK . Acetylated NPM1 localizes in the nucleoplasm and regulates transcriptional activation of genes implicated in oral cancer manifestation. Mol Cell Biol 2009; 29: 5115–5127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Swaminathan V, Kishore AH, Febitha KK, Kundu TK . Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Mol Cell Biol 2005; 25: 7534–7545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu X, Liu Z, Jang S-W, Ma Z, Shinmura K, Kang S et al. Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival. Proc Natl Acad Sci USA 2007; 104: 9679–9684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bolli N, Nicoletti I, De Marco MF, Bigerna B, Pucciarini A, Mannucci R et al. Born to be exported: COOH-terminal nuclear export signals of different strength ensure cytoplasmic accumulation of nucleophosmin leukemic mutants. Cancer Res 2007; 67: 6230–6237.

    Article  CAS  PubMed  Google Scholar 

  19. Schnittger S, Bacher U, Haferlach C, Alpermann T, Dicker F, Sundermann J et al. Nucleolar protein B23 has molecular chaperone activities. Leukemia 2011; 25: 615–621.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Kurki S, Peltonen K, Latonen L, Kiviharju TM, Ojala PM, Meek D et al. Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 2004; 5: 465–475.

    Article  CAS  PubMed  Google Scholar 

  22. Gao H, Jin S, Song Y, Fu M, Wang M, Liu Z et al. B23 regulates GADD45a nuclear translocation and contributes to GADD45a-induced cell cycle G2-M arrest. J Biol Chem 2005; 280: 10988–10996.

    Article  CAS  PubMed  Google Scholar 

  23. Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L et al. GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci USA 1999; 96: 3706–3711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sherr CJ . Divorcing ARF and p53: an unsettled case. Nat Rev Cancer 2006; 6: 663–673.

    Article  CAS  PubMed  Google Scholar 

  25. Kuo M-L, den Besten W, Bertwistle D, Roussel MF, Sherr CJ . N-terminal polyubiquitination and degradation of the Arf tumor suppressor. Genes Dev 2004; 18: 1862–1874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bertwistle D, Bertwistle D, Sugimoto M, Sugimoto M, Sherr CJ, Sherr CJ . Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Mol Cell Biol 2004; 24: 985–996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D . Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1999; 1: 20–26.

    Article  CAS  PubMed  Google Scholar 

  28. Leong SM, Tan BX, Ahmad BB, Yan T, Chee LY, Ang ST et al. Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition. Blood 2010; 116: 3286–3296.

    Article  CAS  PubMed  Google Scholar 

  29. Li Z, Boone D, Hann SR . Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Proc Natl Acad Sci USA 2008; 105: 18794–18799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bonetti P, Davoli T, Sironi C, Amati B, Pelicci PG, Colombo E . Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7y. J Cell Biol 2008; 182: 19–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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  PubMed  Google Scholar 

  32. Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R et al. Clinical characteristics and prognostic implications of. Neoplasia 2005; 106: 2854–2861.

    CAS  Google Scholar 

  33. Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006; 107: 4011–4020.

    Article  CAS  PubMed  Google Scholar 

  36. Jeon Y, Seo SW, Park S, Park S, Kim SY, Ra EK et al. Identification of two novel NPM1 mutations in patients with acute myeloid Leukemia. Ann Lab Med 2013; 33: 60–64.

    Article  CAS  PubMed  Google Scholar 

  37. Verhaak RGW, 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: 3747–3755.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang Y, Zhang M, Yang L, Xiao Z . NPM1 mutations in myelodysplastic syndromes and acute myeloid leukemia with normal karyotype. Leuk Res 2007; 31: 109–111.

    Article  CAS  PubMed  Google Scholar 

  39. Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med 2016; 374: 422–433.

    Article  CAS  PubMed  Google Scholar 

  40. 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  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Colombo E, Martinelli P, Zamponi R, Shing DC, Bonetti P, Luzi L et al. Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant. Cancer Res 2006; 66: 3044–3050.

    Article  CAS  PubMed  Google Scholar 

  43. 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  PubMed  Google Scholar 

  44. Grisendi S, Bernardi R, Rossi M, Cheng K, Khandker L, Manova K et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature 2005; 437: 147–153.

    Article  CAS  PubMed  Google Scholar 

  45. Colombo E, Bonetti P, Denchi EL, Martinelli P, Zamponi R, Helin K et al. Nucleophosmin is required for DNA integrity and p19 Arf protein stability. Mol Cell Biol 2005; 25: 8874–8886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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: 1593–1598.

    Article  CAS  PubMed  Google Scholar 

  47. Sportoletti P, Grisendi S, Majid SM, Cheng K, Clohessy JG, Viale A et al. Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 2008; 111: 3859–3862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cheng K, Sportoletti P, Ito K, Clohessy JG, Teruya-feldstein J, Kutok JL et al. The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model. Blood 2010; 115: 3341–3345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sportoletti P, Varasano E, Rossi R, Bereshchenko O, Cecchini D, Gionfriddo I et al. The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model. Blood 2013; 121: 3447–3458.

    Article  CAS  PubMed  Google Scholar 

  50. 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  PubMed  Google Scholar 

  51. Martelli MP, Manes N, Pettirossi V, Liso A, Pacini R, Mannucci R et al. Absence of nucleophosmin leukaemic mutants in B and T cells from AML with NPM1 mutations: implications for the cell of origin of NPMc+ AML. Leukemia 2008; 22: 195–198.

    Article  CAS  PubMed  Google Scholar 

  52. Liso A, Bogliolo A, Freschi V, Martelli MP, Pileri SA, Santodirocco M 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.

    Article  CAS  PubMed  Google Scholar 

  53. Caudill JSC, Sternberg AJ, Li CY, Tefferi A, Lasho TL, Steensma DP . C-terminal nucleophosmin mutations are uncommon in chronic myeloid disorders. Br J Haematol 2006; 133: 638–641.

    Article  CAS  PubMed  Google Scholar 

  54. Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008; 111: 2776–2784.

    Article  CAS  PubMed  Google Scholar 

  55. Chou WC, Tang JL, Lin LI, Yao M, Tsay W, Chen CY et al. Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res 2006; 66: 3310–3316.

    Article  CAS  PubMed  Google Scholar 

  56. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik V, Paschka P, Roberts N et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016; 374: 2209–2221.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Haferlach C, Mecucci C, Schnittger S, Kohlmann A, Mancini M, Cuneo A 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.

    Article  CAS  PubMed  Google Scholar 

  58. Schnittger S, Kern W, Tschulik C, Weiss T, Dicker F, Haferlach C et al. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood 2009; 114: 2220–2231.

    Article  CAS  PubMed  Google Scholar 

  59. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506: 328–333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Alcalay M, Tiacci E, Bergomas R, Bigerna B, Venturini E, Minardi SP et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin shows a distinct gene expression profile characterized by of genes involved in maintenance. Blood 2005; 106: 899–902.

    Article  CAS  PubMed  Google Scholar 

  61. de Propris MS, Raponi S, Diverio D, Milani ML, Meloni G, Falini B et al. High CD33 expression levels in acute myeloid leukemia cells carrying the nucleophosmin (NPM1) mutation. Haematologica 2011; 96: 1548–1551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Gorlich D et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood 2016; 128: 686–698.

    Article  CAS  PubMed  Google Scholar 

  63. Yang L, Rau R, Goodell MA . DNMT3A in haematological malignancies. Nat Rev Cancer 2015; 15: 152–165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kapp-Schwoerer S, Cocciardi S, Kroenke J, Dolnik A, Blatte TJ, Corbacioglu A . Clonal evolution in NPM1 mutated acute myeloid leukemia (AML). Blood 2015; 126: 1381.

    Google Scholar 

  65. Krönke J, Bullinger L, Teleanu V, Tsch F, Gaidzik VI, Michael WMK et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood 2013; 122: 100–109.

    Article  CAS  PubMed  Google Scholar 

  66. Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371: 2477–2487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371: 2488–2498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20: 1472–1478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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  CAS  Google Scholar 

  70. Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol 2010; 28: 570–577.

    Article  CAS  PubMed  Google Scholar 

  71. Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE . Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol 2010; 28: 2739–2747.

    Article  CAS  PubMed  Google Scholar 

  72. Wandt H, Haferlach T . Letter to the Editor: WHO classification of myeloid neoplasms and leukemia. Blood 2010; 115: 748–749.

    Article  CAS  PubMed  Google Scholar 

  73. Haferlach T, Schoch C, Löffler H, Gassmann W, Kern W, Schnittger S et al. Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML. J Clin Oncol 2003; 21: 256–265.

    Article  PubMed  Google Scholar 

  74. Wandt H, Scha U, Kroschinsky F, Prange-Krex G, Mohr B, Thiede C et al. MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients. Blood 2008; 111: 1855–1862.

    Article  CAS  PubMed  Google Scholar 

  75. Falini B, Macijewski K, Weiss T, Bacher U, Schnittger S, Kern W et al. Multilineage dsplasia has no impact on biologic, clinicopathologic and prognostic features of AML with mutated nucleophosmin (NPM1). Blood 2010; 115: 3776–3786.

    Article  CAS  PubMed  Google Scholar 

  76. Pabst T, Eyholzer M, Fos J, Mueller BU . Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer 2009; 100: 1343–1346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wouters BJ, Löwenberg B, Erpelinck-Verschueren CAJ, Van Putten WLJ, Valk PJM, Delwel R . Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009; 113: 3088–3091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    Article  CAS  PubMed  Google Scholar 

  79. Schlenk RF, Dohner K, Kneba M, Gotze K, Hartmann F, Del Valle F 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.

    Article  CAS  PubMed  Google Scholar 

  80. Schlenk RF, Dohner K, Krauter J, Gaidzik VI, Paschka P, Heuser M et al. All-trans retinoic acid improves outcome in younger adult patients with nucleophosmin-1 mutated acute myeloid leukemia - results of the AMLSG 07-04 Randomized Treatment Trial. Blood Abstr 2011; 118: 80.

    Article  CAS  Google Scholar 

  81. El Hajj H, Dassouki Z, Berthier C, Raffoux E, Ades L, Legrand O et al. Retinoic acid and arsenic trioxide trigger degradation of mutated NPM-1 resulting in apoptosis of AML cells. Blood 2015; 125: 3447–3455.

    Article  CAS  PubMed  Google Scholar 

  82. Martelli MP, Gionfriddo I, Mezzasoma F, Milano F, Pierangeli S, Mulas F et al. Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells. Blood 2015; 125: 3455–3465.

    Article  CAS  PubMed  Google Scholar 

  83. Lambert J, Lambert J, Nibourel O, Pautas C, Hayette S, Cayuela J-M et al. MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin. Oncotarget 2014; 5: 6280–6288.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Olombel G, Guerin E, Guy J, Perrot J-Y, Dumexy F, de Labarthe A et al. Letter to the Editor: The level of blast CD33 expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia. Blood 2016; 127: 2155–2157.

    Article  CAS  Google Scholar 

  85. Falini B, Brunetti L, Martelli MP . Letter to the Editor: Dactinomycin in NPM1-mutated acute myeloid leukemia. N Engl J Med 2015; 372: 1180–1182.

    Article  Google Scholar 

  86. Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100: 4372–4380.

    Article  CAS  PubMed  Google Scholar 

  87. Gale RE, Lamb K, Allen C, El-Sharkawi D, Stowe C, Jenkinson S et al. Simpson’s paradox and the impact of different DNMT3A mutations on outcome in younger adults with acute myeloid leukemia. J Clin Oncol 2015; 33: 2072–2083.

    Article  CAS  PubMed  Google Scholar 

  88. Hou H-A, Kuo Y-Y, Liu C-Y, Chou W-C, Lee MC, Chen C-Y et al. DNMT3A mutations in acute myeloid leukemia-stability during disease evolution and the clinical implication. Blood 2011; 119: 559–569.

    Article  CAS  PubMed  Google Scholar 

  89. Thol F, Damm F, Lüdeking A, Winschel C, Wagner K, Morgan M et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 2011; 29: 2889–2896.

    Article  CAS  PubMed  Google Scholar 

  90. Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, Rockova V, Sanders M, Abbas S et al. Mutant DNMT3A: a new marker of poor prognosis in acute myeloid leukemia. Blood 2012; 119: 5824–5832.

    Article  CAS  PubMed  Google Scholar 

  91. Renneville A, Boissel N, Nibourel O, Berthon C, Helevaut N, Gardin C et al. Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia 2012; 26: 1247–1254.

    Article  CAS  PubMed  Google Scholar 

  92. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–2433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland CM, Schneider S et al. DNMT3A mutations associate with shorter survival and modulate prognostic impact of mutation NPM1: an analysis based on comprehensive mutational screening of 660 AML patients treated on German AML cooperative group (AMLCG) trials. Blood 2015; 126: 3815.

    Google Scholar 

  94. Leonard J, Dunlap J, Neff TL, Warrick A, Fei Y, Press RD et al. Mutations modifying risk in NPM1+ AML. Blood 2015; 126: 2592.

    Article  CAS  Google Scholar 

  95. Wouters BJ, Lowenberg B, Delwel R . A decade of genome-wide gene expression profiling in acute myeloid leukemia: flashback and prospects. Blood Rev 2009; 113: 291–298.

    Article  CAS  Google Scholar 

  96. Kohlmann A, Bullinger L, Thiede C, Schaich M, Schnittger S, Döhner K et al. Gene expression profiling in AML with normal karyotype can predict mutations for molecular markers and allows novel insights into perturbed biological pathways. Leuk Lett 2010; 24: 1216–1220.

    Article  CAS  Google Scholar 

  97. Grimwade D, Freeman SD . Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for 'prime time'? Blood 2014; 124: 3345–3355.

    Article  CAS  PubMed  Google Scholar 

  98. Krönke J, Schlenk RF, Jensen K-O, Tschürtz F, Corbacioglu A, Gaidzik VI et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol 2011; 29: 2709–2716.

    Article  PubMed  Google Scholar 

  99. Shayegi N, Kramer M, Bornhäuser M, Schaich M, Schetelig J, Röllig C et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood 2013; 122: 83–92.

    Article  CAS  PubMed  Google Scholar 

  100. Hubmann M, Kohnke T, Hoster E, Schneider S, Dufour A, Zellmeier E et al. Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse. Haematologica 2014; 99: 1317–1325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhäuser M, Juliusson G et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol 2012; 9: 579–590.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

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

    E M Heath, S M Chan, M D Minden, T Murphy, L I Shlush & A D Schimmer

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

    E M Heath, M D Minden, T Murphy & A D Schimmer

  3. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    L I Shlush

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  1. E M Heath
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  2. S M Chan
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  3. M D Minden
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  4. T Murphy
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  5. L I Shlush
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  6. A D Schimmer
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Correspondence to A D Schimmer.

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Heath, E., Chan, S., Minden, M. et al. Biological and clinical consequences of NPM1 mutations in AML. Leukemia 31, 798–807 (2017). https://doi.org/10.1038/leu.2017.30

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  • DOI: https://doi.org/10.1038/leu.2017.30

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