Annals of Hematology

, Volume 88, Issue 2, pp 159–166

Nucleophosmin mutations in Chinese adults with acute myelogenous leukemia

Original Article

Abstract

Recently, mutations in the nucleophosmin (NPM1) gene were detected in 50–60% of adult acute myelogenous leukemia (AML) patients, mainly with a normal karyotype. In this study, we detected typical NPM1 mutations (types A, B, D) in untreated Chinese AML patients using real-time quantitative polymerase chain reaction (RQ-PCR) followed by sequence analysis. The detection rate of NPM1 mutations in 220 AML patients was 16.4%, including 107 (14.2%) with the French–American–British (FAB) subtype M2, 43 (2.3%) with M3, and 52 (30.8%) with M4/M5. Only one case each with an NPM1 mutation was detected in four M0, seven M1, five M6, and two M7 cases. Eight patients were followed up after treatment, and five patients in hematologic remission continued to test negative for NPM1 mutations within 2–14 months of follow-up. Sequence analysis revealed that all the 36 positive cases were heterozygous for the mutation with 4-bp insertions at nt 959; the 36 cases included 29 (80.6%) cases with type A, four (11.1%) cases with type B, and one rare DD-3 mutation. We also detected two new mutations, namely, CTCG and CAAG insertions, named BJ-01 and BJ-02, respectively. Further, 38.9% (14/36) patients with NPM1 mutations simultaneously exhibited internal tandem duplications in the FLT3 gene, and 66.7% (22/33) patients did not express CD34. The results demonstrated that RQ-PCR was a reliable and sensitive method for detecting NPM1 mutations, for screening AML, and for the quantitative analysis of minimal residual diseases.

Keywords

NPM1 mutation Acute myelogenous leukemia Real-time quantitative PCR 

References

  1. 1.
    Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352:254–266. doi:10.1056/NEJMoa041974 PubMedCrossRefGoogle Scholar
  2. 2.
    Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF et al (2005) Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106:3733–3739. doi:10.1182/blood-2005-06-2248 PubMedCrossRefGoogle Scholar
  3. 3.
    Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R et al (2005) Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood 106:2854–2861. doi:10.1182/blood-2005-04-1733 PubMedCrossRefGoogle Scholar
  4. 4.
    Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens 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(12):3747–3754. doi:10.1182/blood-2005-05-2168 PubMedCrossRefGoogle Scholar
  5. 5.
    Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM et al (2005) Prevalence, clinical profile and prognosis of NPM mutations in AML with normal karyotype. Blood 106:3618–3620. doi:10.1182/blood-2005-05-2174 PubMedCrossRefGoogle Scholar
  6. 6.
    Qin Y-Z, Liu Y-R, Li J-L, Fu J-Y, Chang Y, Ruan G-R, Wang H, Qiu J-Y, Lu D-P, Chen S-S (2003) Follow-up Detection of M-bcr/ abl and m-bcr/ abl fusion transcripts in chronic myeloid leukemia patients after allogeneic hematopoietic stem cell transplantation. Zhongguo Shi Yan Xue Ye Xue Za Zhi 11:368–371PubMedGoogle Scholar
  7. 7.
    Gorello P, Cazzaniga G, Alberti F, Dell'Oro MG, Gottardi E, Specchia G et al (2006) Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 20:1103–1108. doi:10.1038/sj.leu.2404149 PubMedCrossRefGoogle Scholar
  8. 8.
    Qin YZ, Li JL, Zhu HH, Ruan GR, Li LD, Zhang Y et al (2006) Monitoring bcr-abl mRNA levels by real-time quantitative RT-PCR in chronic myeloid leukemia patients after hematopoietic stem cell transplantation. Zhonghua Xue Ye Xue Za Zhi 27(8):511–514PubMedGoogle Scholar
  9. 9.
    Van der Velden VH, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJ (2003) Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia 17:1013–1034. doi:10.1038/sj.leu.2402922 PubMedCrossRefGoogle Scholar
  10. 10.
    Sheikhha MH, Awan A, Tobal K, Liu Yin JA (2003) Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol J 4(1):41–46. doi:10.1038/sj.thj.6200224 PubMedCrossRefGoogle Scholar
  11. 11.
    Liu YR, Yu H, Chang Y, Chen SS (2003) The application of 4-color fluorescence labeling antibodies and its significance in immunophenotyping for leukemia by flow cytometer. Zhongguo Shi Yan Xue Ye Xue Za Zhi 10(5):423–427Google Scholar
  12. 12.
    Zhang Y, He Q, Huang XJ, Jiang H, Yang SM, Lu J et al (2007) Cytogenetic study on eosinophilia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 15(3):454–457PubMedGoogle Scholar
  13. 13.
    Falini B, Nicoletti I, Martelli MF, Mecucci C (2006) Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc_AML): biologic and clinical features. Blood 109(3):874–885. doi:10.1182/blood-2006-07-012252 PubMedCrossRefGoogle Scholar
  14. 14.
    Chou WC, Tang JL, Lin LI, Yao M, Tsay W, Chen CY et al (2006) Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res 66(6):3310–3316. doi:10.1158/0008-5472.CAN-05-4316 PubMedCrossRefGoogle Scholar
  15. 15.
    Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M et al (2006) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 107:4011–4020. doi:10.1182/blood-2005-08-3167 PubMedCrossRefGoogle Scholar
  16. 16.
    Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker FG, Corbacioglu A 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(12):3740–3746. doi:10.1182/blood-2005-05-2164 PubMedCrossRefGoogle Scholar
  17. 17.
    Grisendi S, Mecucci C, Falini B, Pandolfi PP (2006) Nucleophosmin and cancer. Nat Rev Cancer 6(7):493–505. doi:10.1038/nrc1885 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Peking University Institute of Hematology and People’s HospitalBeijingChina

Personalised recommendations