DOI QR코드

DOI QR Code

Prognostic Involvement of Nucleophosmin Mutations in Acute Myeloid Leaukemia

  • Shahab, Sadaf (Molecular Biology, Pure and Applied Research, National Institute Blood Diseases and Bone Marrow Transplantation) ;
  • Shamsi, Tahir Sultan (Department of Haematology, National Institute Blood Diseases and Bone Marrow Transplantation) ;
  • Ahmed, Nuzhat (Molecular Biology, Pure and Applied Research, National Institute Blood Diseases and Bone Marrow Transplantation)
  • Published : 2013.10.30

Abstract

Nucleophosmin (NPM1) is a protein of highly conserved nature which works as a molecular chaperone and is mostly found in nucleoli. NPM also involved in the maturation of preribosomes and duplication of centrosomes. Furthermore, it is also active in control and regulation of the ARF-p53 tumor suppressor pathway. A high rate of incidence and prognostic involvement is reported by various authors in AML patients. In AML it behaves as a favorable prognostic marker. NPM mutations are more frequently associated with normal-karyotype AML and are usually absent in patients having abnormal or poor cytogenetic. NPM mutations are not frequent in other hematopoietic tumors. Two main types of mutations have been described to date. Both of these cause abnormal cytoplasmic localization of NPM1. Their high incidence rate in normal karyoptype and their favorable nature m ake those mutations hot spot or front face mutations which should be checked before treatment starts.

Keywords

Nucleophosmin;prognostic marker;AML;normal karyotype;NPM mutations;exon 12

References

  1. Ahmad F, Mandava S, Das BR (2009). Mutations of NPM1 gene in de novo acute myeloid leukaemia: determination of incidence, distribution pattern and identification of two novel mutations in Indian population. Hematol Oncol, 27, 90-7. https://doi.org/10.1002/hon.883
  2. Albiero E, Madeo D, Giaretta I, et al (2006). A novel mutation in the exon 11 of nucleophosmin (NPM1) gene leads to a truncated form of the protein lacking the C-terminal NES-motif. Haematologica, 91, 237.
  3. Ammatuna E, Noguera NI, Zangrilli D, et al (2005). Rapid detection of nucleophosmin (NPM1) mutations in acute myeloid leukemia by denaturing HPLC. Clin Chem, 51, 2165-7. https://doi.org/10.1373/clinchem.2005.055707
  4. Becker H, Marcucci G, Maharry K, et al (2010). Favorable prognostic impactof NPM1 mutations in older patients withcytogenetically normal de novo acute myeloidleukemia and associated gene- and microRNA-expression signatures: a cancer andleukemia group B study. J Clin Oncol, 28, 596-604. https://doi.org/10.1200/JCO.2009.25.1496
  5. Bertwistle D, Sugimoto M, Sherr CJ (2004). Physical and functional interactions of the ARF tumor suppressor protein with nucleophosmin/B23. Mol Cell Biol, 24, 985-96. https://doi.org/10.1128/MCB.24.3.985-996.2004
  6. Boonthimat C, Thongnoppakhun W, Auewarakul CU (2008). Nucleophosmin mutation in Aoutheast Asian acute myeloid leukemia: eight novel variants, FLT3 coexistence and prognostic impact of NPM1/FLT3 mutations. Haematologica, 93, 1565-9. https://doi.org/10.3324/haematol.12937
  7. Boissel N, Renneville A, Biggio V, et al (2005). Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood, 106, 3618-20. https://doi.org/10.1182/blood-2005-05-2174
  8. Bolli N, Nicoletti I, De Marco MF, et al (2007). Born to be exported: COOH-terminal nuclear export signals of different strength ensure cytoplasmic accumulation of nucleophosmin leukemic mutants. Cancer Res, 67, 6230-7. https://doi.org/10.1158/0008-5472.CAN-07-0273
  9. Bonetti P, Davoli T, Sironi C, et al (2008). Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma. J Cell Biol, 182, 19-26. https://doi.org/10.1083/jcb.200711040
  10. Brown P, McIntyre E, Rau R, et al (2007). The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood, 110, 979-85. https://doi.org/10.1182/blood-2007-02-076604
  11. Braoudaki M, Chrissa P, Katerina K, et al (2010). The frequency of NPM1 mutations in childhood acute myeloid leukemia. J Hematol Oncol, 3, 41. https://doi.org/10.1186/1756-8722-3-41
  12. Cazzaniga G, Dell'Oro MG, Mecucci C, et al (2005). Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood, 106, 1419-22. https://doi.org/10.1182/blood-2005-03-0899
  13. Chang JH, Olson MO (1990). Structure of the gene for rat nucleolar protein B23. J Biol Chem, 265, 18227-33.
  14. Chou WC, Tang JL, Lin LI, et al (2006). Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res, 66, 3310-6. https://doi.org/10.1158/0008-5472.CAN-05-4316
  15. Dalia N, Mohammed AR, Dominique B (2011). Incidence and prognostic value of NPM1 and FLT3 gene mutations in AML with normal karyotype. Open J Hematol, 5, 14-20. https://doi.org/10.2174/1874276901105010014
  16. Colombo E, Bonetti P, Lazzerini Denchi E, et al (2005). Nucleophosmin is required for DNA integrity and p19ARF protein stability. Mol Cell Biol, 25, 8874-86. https://doi.org/10.1128/MCB.25.20.8874-8886.2005
  17. Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG (2002). Nucleophosmin regulates the stability andtranscriptional activity of p53. Nat Cell Biol, 4, 529-33. https://doi.org/10.1038/ncb814
  18. Colombo E, Martinelli P, Zamponi R, et al (2006). Delocalization and destabilization of the ARF tumor suppressor by the leukemia-associated NPM mutant. Cancer Res, 66, 3044-50. https://doi.org/10.1158/0008-5472.CAN-05-2378
  19. den Besten W, Kuo ML, Williams RT, Sherr CJ (2005). Myeloid leukemia-associated nucleophosmin mutants perturb p53-dependent and independent activities of the ARF tumor suppressor protein. Cell Cycle, 4, 1593-8. https://doi.org/10.4161/cc.4.11.2174
  20. Dohner K, Schlenk RF, Habdank M, et al (2005). Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood, 106, 3740-6. https://doi.org/10.1182/blood-2005-05-2164
  21. Falini B, Bolli N, Liso A, et al (2009). Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia, 23, 1731-43. https://doi.org/10.1038/leu.2009.124
  22. Falini B, Bolli N, Shan J, et al (2006). Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMcp AML. Blood, 107, 4514-23. https://doi.org/10.1182/blood-2005-11-4745
  23. Falini B, Mecucci C, Tiacci E, et al (2005). Cytoplasmic nucleophosmin in acute myelogenous leukemia with abnormal karyotype. N Engl J Med, 352, 254-66. https://doi.org/10.1056/NEJMoa041974
  24. Gorello P, Cazzaniga G, Alberti F, et al (2006). Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia, 20, 1103-8. https://doi.org/10.1038/sj.leu.2404149
  25. Falini B, Nicoletti I, Bolli N, et al (2007). Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. Haematologica, 92, 519-32. https://doi.org/10.3324/haematol.11007
  26. Falini B, Martelli MP, Bolli N (2011). Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? Blood, 117, 1109-20. https://doi.org/10.1182/blood-2010-08-299990
  27. Gjerset RA, Bandyopadhyay K (2006). Regulation ofp14ARF through subnuclear compartmentalization. Cell Cycle, 5, 686-90. https://doi.org/10.4161/cc.5.7.2623
  28. Grisendi S, Bernardi R, Rossi M, et al (2005). Role of nucleophosmin in embryonic development and tumorigenesis. Nature, 437, 147-53. https://doi.org/10.1038/nature03915
  29. Haferlach C, Mecucci C, Schnittger S, et al (2009). AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features. Blood, 114, 3024-32. https://doi.org/10.1182/blood-2009-01-197871
  30. Hafez M, Ye F, Jackson K, et al (2010). Performance and clinical evaluation of a sensitive multiplex assay for the rapid detection of common NPM1 mutations. J Mol Diagn, 12, 629-35. https://doi.org/10.2353/jmoldx.2010.090219
  31. Herrera JE, Correia JJ, Jones AE, Olson MO (1996). Sedimentation analyses of the salt- and divalent metal ion induced oligomerization of nucleolarprotein B23. Biochemistry, 35, 2668-73. https://doi.org/10.1021/bi9523320
  32. Hingorani K, Szebeni A, Olson MO (2000). Mapping the functional domains of nucleolar protein B23. J Biol Chem, 275, 24451-7. https://doi.org/10.1074/jbc.M003278200
  33. Huang Q, Chen W, Gaal KK, et al (2008). A rapid, one step assay for simultaneous detection of FLT3/ITDand NPM1 mutations in AML with normal cytogenetics. Br J Haematol, 142, 480-501. https://doi.org/10.1111/j.1365-2141.2008.07194.x
  34. Kim YK, Kim HN, Lee SR, et al (2010). Prognostic significance of nucleophosmin mutations and FLT3 internal tandem duplication in adult patients with cytogenetically normal acute myeloid leukemia. Korean J Hematol, 45, 36-45. https://doi.org/10.5045/kjh.2010.45.1.36
  35. Jeon Y, Seo SW, Park S, et al (2013). Identification of two novel NPM1 mutations in patients with acute myeloid leukemia. Ann Lab Med, 33, 60-4. https://doi.org/10.3343/alm.2013.33.1.60
  36. Kassem N, Hamid AA, Attia T, et al (2011). Novel mutations of the nucleophosmin (NPM-1) gene in Egyptian patients with acute myeloid leukemia: a pilot study. J Egypt Natl Cancer Inst, 23, 73-8. https://doi.org/10.1016/j.jnci.2011.09.003
  37. Kazem AH, Mikhael IL, Ghanem AM (2011). Cytoplasmic nucleophosmin (cNPM) in acute myeloid leukaemia: Relation to disease characteristics. AJM, 47, 225-35.
  38. Krstovski N, Tosic N, Janic D, et al (2010). Incidence of FLT3 and nucleophosmin genemutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature. Med Oncol, 27, 640-5. https://doi.org/10.1007/s12032-009-9261-5
  39. Kurki S, Peltonen K, Latonen L, et al (2004). Nucleolarprotein NPM interacts with HDM2 and protectstumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell, 5, 465-75. https://doi.org/10.1016/S1535-6108(04)00110-2
  40. Kuo ML, den Besten W, Bertwistle D, Roussel MF, Sherr CJ (2004). N-terminal polyubiquitination and degradation of the ARF tumor suppressor. Genes Dev, 18, 1862-74. https://doi.org/10.1101/gad.1213904
  41. Kuzmanovic M, Tosic N, Colovic N, et al (2012). Mutations in Serbian adult patients with acute myeloid leukemia. Acta Haematol, 128, 203-12. https://doi.org/10.1159/000339506
  42. Laughlin TS, Becker MW, Liesveld JL, et al (2008). Rapid method for detection of mutations in the nucleophosmin gene in acute myeloid leukemia. J Molecular Diag, 10, 338-45. https://doi.org/10.2353/jmoldx.2008.070175
  43. Luo J, Qi C, Xu W, et al (2010). Cytoplasmic expression of nucleophosmin accurately predicts mutation in the nucleophosmin gene in patients with acute myeloid leukemia and normal karyotype. Am J Clin Pathol, 133, 34-40. https://doi.org/10.1309/AJCPCI1FFE2DRXIV
  44. Lee SY, Park JH, Kim S, et al (2005). A proteomics approach for the identification of nucleophosmin and heterogeneous nuclear ribonucleoprotein C1/C2 as chromatin- binding proteins in response to DNA double-strand breaks. Biochem J, 388, 7-15. https://doi.org/10.1042/BJ20042033
  45. Li J, Sejas DP, Rani R, et al (2006). Nucleophosmin regulates cell cycle progression and stress response in hematopoietic stem/progenitor cells. J Biol Chem, 281, 16536-45. https://doi.org/10.1074/jbc.M601386200
  46. Lin Ll, Lin TC, Chou WC, et al (2006). A novel fluorescencebased multiplex PCR assay for rapid simultaneous detection of CEBPA mutations and NPM mutations in patients with acute myeloid leukemias. Leukemia, 20, 1899-903. https://doi.org/10.1038/sj.leu.2404331
  47. Mariano AR, Colombo E, Luzi L, et al (2006). Cytoplasmic localization of NPM in myeloid leukemias is a functional nuclear export signal. Oncogene, 25, 4376-80. https://doi.org/10.1038/sj.onc.1209453
  48. Mattsson G, Turner SH, Cordell J, et al (2010). Can cytoplasmic nucleophosmin be detected by immunocytochemical staining of cell smears in acute myeloid leukemia? Haematologica, 95, 670-3. https://doi.org/10.3324/haematol.2009.011817
  49. Micol JB, Boissel N, Renneville A, (2009) et al. The role of cytogenetic abnormalities in acute myeloid leukemia with NPM1 mutations and no FLT3 internal tandem duplication. Blood, 114, 4601-2. https://doi.org/10.1182/blood-2009-07-230995
  50. Mori Y, Yoshimoto G, Kumano T, et al (2007). Distinctive expression of myelomonocytic markers and down-regulation of CD34 in acute myelogenous leukaemia with FLT3 tandem duplication and nucleophosmin mutation. Eur J Hematol, 79, 17-24. https://doi.org/10.1111/j.1600-0609.2007.00866.x
  51. Oppliger Leibundgut E, Porret NA, Bienz Muggli M, et al (2012). Rapid and highly specific screening for NPM1 mutations in acute myeloid leukemia. Ann Hematol, 92, 173-7.
  52. Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD (2007). Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood, 109, 431-48. https://doi.org/10.1182/blood-2006-06-001149
  53. Mullighan CG, Kennedy A, Zhou X, et al (2007). Pediatric acute myeloid leukemia with NPM1 mutations ischaracterised by a gene expression profile with dysregulatedHOX gene expression distinct from MLL-rearranged leukemias. Leukemia, 21, 2000-9. https://doi.org/10.1038/sj.leu.2404808
  54. Okuwaki M, Matsumoto K, Tsujimoto M, Nagata K (2001). Function of nucleophosmin/B23, a nucleolar acidic protein, as a histone chaperone. FEBS Lett, 506, 272-6. https://doi.org/10.1016/S0014-5793(01)02939-8
  55. Ottone T, Ammatuna E, Lavorgna S (2008). An allele-specific rt-PCR assay to detect type A mutation of the nucleophosmin-1 gene in acute myeloid leukemia. J Mol Diagn, 10, 212-6. https://doi.org/10.2353/jmoldx.2008.070166
  56. Palmisano M, Grafone T, Ottaviani E, et al (2007). NPM1 mutations are more stable than FLT3mutations during the course of disease in patients with acute myeloid leukemia. Haematologica, 92, 1268-9. https://doi.org/10.3324/haematol.11202
  57. Roti G, Rosati R, Bonasso R, et al (2006). Denaturing high-performance liquid chromatography: a valid approach for identifying NPM1 mutations in acute myeloid leukemia. J Mol Diagn, 8, 254-9. https://doi.org/10.2353/jmoldx.2006.050098
  58. Ruan GR, Li JL, Qin YZ, et al (2008). Nucleophosmin mutations in Chinese adults with acute myelogenous leukemia. Ann Hematol, 88, 159-66..
  59. Schneider F, Hoster E, Schneider S, et al (2012). Age-dependent frequencies of NPM1 mutationsand FLT3-ITD in patients with normal karyotype AML (NK-AML). Ann Hematol, 91, 9-18. https://doi.org/10.1007/s00277-011-1280-6
  60. Szankasi P, Jama M, Bahler DW (2008). A new DNA-based test for detection of nucleophosmin exon 12 mutations by capillary electrophoresis. J Mol Diagn, 10, 236-41. https://doi.org/10.2353/jmoldx.2008.070167
  61. Schnittger S, Schoch C, Kern W, et al (2005). Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood, 106, 3733-9. https://doi.org/10.1182/blood-2005-06-2248
  62. Shimada A, Taki T, Kubota C, et al (2007). Nonucleophosmin mutations in pediatric acute myeloid leukemiawith normal karyotype: a study of the Japanese childhood AML cooperative study group. Leukemia, 21, 1307. https://doi.org/10.1038/sj.leu.2404625
  63. Suzuki T, Kiyoi H, Ozeki K, et al (2005). Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood, 106, 2854-61. https://doi.org/10.1182/blood-2005-04-1733
  64. Tan A, Westerman DA, Carney DA, et al. (2008) Detection of NPM1 exon 12 mutations and FLT3 - internal tandem duplications by high resolution melting analysis in normal karyotype acute myeloid leukemia. J Hematol Oncol, 1, 10. https://doi.org/10.1186/1756-8722-1-10
  65. Taussig DC, Vargaftig J, Miraki-Moud F, et al (2010). Leukemia initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34fraction. Blood, 115, 1976-84. https://doi.org/10.1182/blood-2009-02-206565
  66. Thiede C, Creutzig E, Reinhardt D, Ehninger G, Creutzig U (2007). Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12. Leukemia, 21, 366-7. https://doi.org/10.1038/sj.leu.2404519
  67. Thiede C, Koch S, Creutzig E, et al (2006). Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood, 107, 4011-20. https://doi.org/10.1182/blood-2005-08-3167
  68. Thiede C, Steudel C, Mohr B, et al (2002). Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 99, 4326-35. https://doi.org/10.1182/blood.V99.12.4326
  69. Verhaak RG, Goudswaard CS, van P W, et al (2005). 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, 106, 3747-54. https://doi.org/10.1182/blood-2005-05-2168
  70. Wu MH, Chang JH, Yung BY (2002). Resistance to UV-induced cellkilling in nucleophosmin/B23 overexpressed NIH 3T3 fibroblasts: enhancement of DNA repair and up-regulation of PCNA in association with nucleophosmin/B23 overexpression. Carcinogenesis, 23, 93-100. https://doi.org/10.1093/carcin/23.1.93

Cited by

  1. Prognostic Role of Nucleophosmin in Colorectal Carcinomas vol.15, pp.5, 2014, https://doi.org/10.7314/APJCP.2014.15.5.2021
  2. Characterisation and Clinical Significance of FLT3-ITD and non-ITD in Acute Myeloid Leukaemia Patients in Kelantan, Northeast Peninsular Malaysia vol.16, pp.12, 2015, https://doi.org/10.7314/APJCP.2015.16.12.4869
  3. Aberrant Expression of HOXA5 and HOXA9 in AML vol.16, pp.9, 2015, https://doi.org/10.7314/APJCP.2015.16.9.3941
  4. Mechanism of the natural product moracin-O derived MO-460 and its targeting protein hnRNPA2B1 on HIF-1α inhibition vol.51, pp.2, 2019, https://doi.org/10.1038/s12276-018-0200-4