Prognostic significance of NPM1 mutations in acute myeloid leukemia: A meta-analysis

Liu,Yanfeng; He,Pengcheng; Liu,Feng; Shi,Lili; Zhu,Huachao; Zhao,Jing; Wang,Yuan; Chen,Xiaoyan; Zhang,Mei

doi:10.3892/mco.2013.222

Prognostic significance of NPM1 mutations in acute myeloid leukemia: A meta-analysis

Authors:
- Yanfeng Liu
- Pengcheng He
- Feng Liu
- Lili Shi
- Huachao Zhu
- Jing Zhao
- Yuan Wang
- Xiaoyan Chen
- Mei Zhang
View Affiliations

Affiliations: Department of Hematology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: December 10, 2013 https://doi.org/10.3892/mco.2013.222
Pages: 275-281

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Nucleophosmin 1 (NPM1) mutations have been identified in a substantial number of patients with acute myeloid leukemia (AML). Favorable outcomes in AML cases with NPM1 mutations have been previously reported. However, widely differing survival estimates have been indicated. Therefore, a meta‑analysis of nine studies including a total of 4509 subjects was performed. The frequency of NPM1 mutations was found to be 6.45-56.08%. NPM1‑mutation type (NPM1‑mt) patients had >2-fold higher odds of achieving complete remission compared with NPM1-wild-type (NPM1‑wt). The summary hazard ratio (HR) of NPM1-mt/NPM1-wt for disease-free survival (DFS) and OS was 0.67 and 0.63, respectively. In conclusion, these findings suggest that the NPM1 mutation has a favorable effect on the outcome for AML. The present meta‑analysis was based on data abstracted from observational studies. However, the results obtained may justify the risk-adapted therapeutic strategies for AML according to the NPM1 status.

View Figures

View References

1	Estey E and Döhner H: Acute myeloid leukemia. Lancet. 368:1894–1907. 2006. View Article : Google Scholar
2	Rubnitz JE, Gibson B and Smith FO: Acute myeloid leukemia. Hematol Oncol Clin North Am. 24:35–63. 2010. View Article : Google Scholar
3	Harrison CJ, Hills RK, Moorman AV, et al: Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol. 28:2674–2681. 2010. View Article : Google Scholar : PubMed/NCBI
4	Grimwade D: The clinical significance of cytogenetic abnormalities in acute myeloid leukaemia. Best Pract Res Clin Haematol. 14:497–529. 2001. View Article : Google Scholar : PubMed/NCBI
5	Döhner H, Estey EH, Amadori S, et al: Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 115:453–474. 2010.PubMed/NCBI
6	Naoe T, Suzuki T, Kiyoi H and Urano T: Nucleophosmin: a versatile molecule associated with hematological malignancies. Cancer Sci. 97:963–969. 2006. View Article : Google Scholar : PubMed/NCBI
7	Borer RA, Lehner CF, Eppenberger HM and Nigg EA: Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell. 56:379–390. 1989. View Article : Google Scholar : PubMed/NCBI
8	Chan WY, Liu QR, Borjigin J, et al: Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth. Biochemistry. 28:1033–1039. 1989. View Article : Google Scholar : PubMed/NCBI
9	Colombo E, Marine JC, Danovi D, Falini B and Pelicci PG: Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol. 4:529–533. 2002. View Article : Google Scholar : PubMed/NCBI
10	Okuda M, Horn HF, Tarapore P, et al: Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell. 103:127–140. 2000. View Article : Google Scholar : PubMed/NCBI
11	Lindstrom MS: NPM1/B23: A multifunctional chaperone in ribosome biogenesis and chromatin remodeling. Biochem Res Int. 2011:1952092011. View Article : Google Scholar : PubMed/NCBI
12	Falini B, Mecucci C, Tiacci E, et al: Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 352:254–266. 2005. View Article : Google Scholar : PubMed/NCBI
13	Verhaak RG, Goudswaard CS, van Putten 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. 106:3747–3754. 2005. View Article : Google Scholar
14	Thiede C, Koch S, Creutzig E, et al: Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 107:4011–4020. 2006. View Article : Google Scholar : PubMed/NCBI
15	Döhner K, Schlenk RF, Habdank M, et al: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 106:3740–3746. 2005.PubMed/NCBI
16	Schnittger S, Schoch C, Kern W, et al: Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 106:3733–3739. 2005. View Article : Google Scholar : PubMed/NCBI
17	Konoplev S, Huang X, Drabkin HA, et al: Cytoplasmic localization of nucleophosmin in bone marrow blasts of acute myeloid leukemia patients is not completely concordant with NPM1 mutation and is not predictive of prognosis. Cancer. 115:4737–4744. 2009. View Article : Google Scholar : PubMed/NCBI
18	Mullighan CG, 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. View Article : Google Scholar
19	Suzuki T, Kiyoi H, Ozeki K, et al: Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood. 106:2854–2861. 2005. View Article : Google Scholar : PubMed/NCBI
20	Gale RE, Green C, Allen C, 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. 111:2776–2784. 2008. View Article : Google Scholar : PubMed/NCBI
21	Becker H, Marcucci G, Maharry K, et al: Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol. 28:596–604. 2010. View Article : Google Scholar
22	Boonthimat C, Thongnoppakhun W and Auewarakul CU: Nucleophosmin mutation in Southeast Asian acute myeloid leukemia: eight novel variants, FLT3 coexistence and prognostic impact of NPM1/FLT3 mutations. Haematologica. 93:1565–1569. 2008. View Article : Google Scholar : PubMed/NCBI
23	Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W and Haferlach T: IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood. 116:5486–5496. 2010.
24	Yan L, Chen S, Liang J, et al: Analysis of NPM1 gene mutations in Chinese adults with acute myeloid leukemia. Int J Hematol. 86:143–146. 2007. View Article : Google Scholar : PubMed/NCBI
25	Haferlach C, Mecucci C, Schnittger S, et al: AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features. Blood. 114:3024–3032. 2009. View Article : Google Scholar : PubMed/NCBI
26	Chen W, Rassidakis GZ, Li J, et al: High frequency of NPM1 gene mutations in acute myeloid leukemia with prominent nuclear invaginations (‘cuplike’ nuclei). Blood. 108:1783–1784. 2006.PubMed/NCBI
27	Paschka P, Schlenk RF, Gaidzik VI, et al: IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 28:3636–3643. 2010. View Article : Google Scholar
28	Koh Y, Park J, Bae EK, et al: Non-A type nucleophosmin 1 gene mutation predicts poor clinical outcome in de novo adult acute myeloid leukemia: differential clinical importance of NPM1 mutation according to subtype. Int J Hematol. 90:1–5. 2009. View Article : Google Scholar
29	Palmisano M, Grafone T, Ottaviani E, Testoni N, Baccarani M and Martinelli G: NPM1 mutations are more stable than FLT3 mutations during the course of disease in patients with acute myeloid leukemia. Haematologica. 92:1268–1269. 2007. View Article : Google Scholar : PubMed/NCBI
30	Zhang Y, Zhang M, Yang L and Xiao Z: NPM1 mutations in myelodysplastic syndromes and acute myeloid leukemia with normal karyotype. Leuk Res. 31:109–111. 2007. View Article : Google Scholar : PubMed/NCBI
31	Wertheim G and Bagg A: Nucleophosmin (NPM1) mutations in acute myeloid leukemia: an ongoing (cytoplasmic) tale of dueling mutations and duality of molecular genetic testing methodologies. J Mol Diagn. 10:198–202. 2008. View Article : Google Scholar
32	Green CL, Koo KK, Hills RK, Burnett AK, Linch DC and 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. 28:2739–2747. 2010. View Article : Google Scholar
33	Noguera NI, Ammatuna E, Zangrilli D, et al: Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia. Leukemia. 19:1479–1482. 2005. View Article : Google Scholar : PubMed/NCBI
34	Burnett AK, Hills RK, Green C, 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. 115:948–956. 2010.
35	Falini B: Therapy-related acute myeloid leukaemia with mutated NPM1: treatment induced or de novo in origin? Leukemia. 22:891–892. 2008. View Article : Google Scholar : PubMed/NCBI
36	Guyatt GH, Oxman AD, Vist GE, et al: GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 336:924–926. 2008. View Article : Google Scholar : PubMed/NCBI
37	Parmar MK, Torri V and Stewart L: Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 17:2815–2834. 1998. View Article : Google Scholar : PubMed/NCBI
38	Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M and Tanimoto M: Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 22:3852–3859. 2004. View Article : Google Scholar : PubMed/NCBI
39	Begg CB and Mazumdar M: Operating characteristics of a rank correlation test for publication bias. Biometrics. 50:1088–1101. 1994. View Article : Google Scholar : PubMed/NCBI
40	Egger M, Davey SG, Schneider M and Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ. 315:629–634. 1997. View Article : Google Scholar : PubMed/NCBI
41	DerSimonian R and Laird N: Meta-analysis in clinical trials. Control Clin Trials. 7:177–188. 1986. View Article : Google Scholar : PubMed/NCBI
42	Yanada M, Matsuo K, Suzuki T, Kiyoi H and Naoe T: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 19:1345–1349. 2005. View Article : Google Scholar : PubMed/NCBI
43	Small D: FLT3 mutations: biology and treatment. Hematol Am Soc Hematol Educ Program. 178–184. 2006. View Article : Google Scholar
44	Kottaridis PD, Gale RE and Linch DC: Flt3 mutations and leukaemia. Br J Haematol. 122:523–538. 2003. View Article : Google Scholar : PubMed/NCBI
45	Feng JH, Guo XP, Chen YY, Wang ZJ, Cheng YP and Tang YM: Prognostic significance of IDH1 mutations in acute myeloid leukemia: a meta-analysis. Am J Blood Res. 2:254–264. 2012.PubMed/NCBI