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Published in: Annals of Hematology 8/2013

01-08-2013 | Original Article

The clinical characteristics and prognostic significance of MN1 gene and MN1-associated microRNA expression in adult patients with de novo acute myeloid leukemia

Authors: Lili Xiang, Man Li, Yan Liu, Jiangnong Cen, Zixing Chen, Xiao Zhen, Xiaobao Xie, Xiangshan Cao, Weiying Gu

Published in: Annals of Hematology | Issue 8/2013

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Abstract

This study aimed to determine the clinical characteristics and prognostic significance of the meningioma 1 (MN1) gene and MN1-associated microRNA expression in Chinese adult de novo acute myeloid leukemia (AML) patients. The expression level of MN1, microRNA-20 (miR-20a), and microRNA-181b (miR-181b) in bone marrow mononuclear cells was measured in 158 newly diagnosed AML patients and 20 cases of normal healthy donors by real-time quantitative reverse transcriptase polymerase chain reaction. All AML patients significantly overexpressed MN1 at the level of 0.01983 (P < 0.001) compared with normal controls. High MN1 expression was associated with spleen involvement (P = 0.037), NPM1 wild type (P = 0.001), lower miR-20a expression levels (P = 0.015), and higher miR-181b expression levels (P = 0.035). MiR-20a (P = 0.029) and miR-181b (P = 0.017) overexpressed in the bone marrow cells of patients with certain subtypes of AML compared with healthy donors. High MN1 expressers had lower complete remission (CR) rates and shorter overall survival (OS) within the Southwest Oncology Group classification. In multivariable models, high MN1 expression was associated with worse CR rates (P = 0.01), relapse-free survival (RFS; P = 0.02), and OS (P = 0.02); high miR-20a expression was associated with higher CR rates (P = 0.008) and longer OS (P = 0.04), whereas high miR-181b expression was associated with lower CR rates (P = 0.03), and shorter RFS (P = 0.045) and OS (P = 0.017). High MN1 expression confers worse prognosis in Chinese adult patients with de novo AML. MN1 gene and MN1-associated microRNAs provide clinical prognosis of AML patients and may refine their molecular risk classification.
Literature
1.
go back to reference Lekanne Deprez RH, Riegman PH, Groen NA et al (1995) Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma. Oncogene 10:1521–1528PubMed Lekanne Deprez RH, Riegman PH, Groen NA et al (1995) Cloning and characterization of MN1, a gene from chromosome 22q11, which is disrupted by a balanced translocation in a meningioma. Oncogene 10:1521–1528PubMed
2.
go back to reference van Wely KH, Molijn AC, Buijs A et al (2003) The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription. Oncogene 22:699–709PubMedCrossRef van Wely KH, Molijn AC, Buijs A et al (2003) The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription. Oncogene 22:699–709PubMedCrossRef
3.
go back to reference Sutton AL, Zhang X, Ellison TI et al (2005) The 1,25(OH)2D3-regulated transcription factor MN1 stimulates vitamin D receptor-mediated transcription and inhibits osteoblastic cell proliferation. Mol Endocrinol 19:2234–2244PubMedCrossRef Sutton AL, Zhang X, Ellison TI et al (2005) The 1,25(OH)2D3-regulated transcription factor MN1 stimulates vitamin D receptor-mediated transcription and inhibits osteoblastic cell proliferation. Mol Endocrinol 19:2234–2244PubMedCrossRef
4.
go back to reference Carella C, Bonten J, Sirma S et al (2007) MN1 overexpression is an important step in the development of inv(16) AML. Leukemia 21:1679–1690PubMedCrossRef Carella C, Bonten J, Sirma S et al (2007) MN1 overexpression is an important step in the development of inv(16) AML. Leukemia 21:1679–1690PubMedCrossRef
5.
go back to reference Golub TR, Slonim DK, Tamayo P et al (1999) Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286:531–537PubMedCrossRef Golub TR, Slonim DK, Tamayo P et al (1999) Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286:531–537PubMedCrossRef
6.
go back to reference Heuser M, Argiropoulos B, Kuchenbauer F et al (2007) MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood 110:1639–1647PubMedCrossRef Heuser M, Argiropoulos B, Kuchenbauer F et al (2007) MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood 110:1639–1647PubMedCrossRef
7.
go back to reference Saito Y, Jones PA (2006) Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5:2220–2222PubMedCrossRef Saito Y, Jones PA (2006) Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5:2220–2222PubMedCrossRef
8.
go back to reference Lytle JR, Yario TA, Steitz JA (2007) Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci U S A 104:9667–9672PubMedCrossRef Lytle JR, Yario TA, Steitz JA (2007) Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci U S A 104:9667–9672PubMedCrossRef
9.
go back to reference Byrd JC, Mrozek K, Dodge RK et al (2002) Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325–4336PubMedCrossRef Byrd JC, Mrozek K, Dodge RK et al (2002) Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325–4336PubMedCrossRef
10.
go back to reference Grimwade D, Walker H, Oliver F et al (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92:2322–2333PubMed Grimwade D, Walker H, Oliver F et al (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92:2322–2333PubMed
11.
go back to reference Slovak ML, Kopecky KJ, Cassileth PA et al (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96:4075–4083PubMed Slovak ML, Kopecky KJ, Cassileth PA et al (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96:4075–4083PubMed
12.
13.
go back to reference Heuser M, Beutel G, Krauter J et al (2006) High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood 108:3898–3905PubMedCrossRef Heuser M, Beutel G, Krauter J et al (2006) High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood 108:3898–3905PubMedCrossRef
14.
go back to reference Langer C, Marcucci G, Holland KB et al (2009) Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 27:3198–3204PubMedCrossRef Langer C, Marcucci G, Holland KB et al (2009) Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 27:3198–3204PubMedCrossRef
15.
go back to reference Schetter AJ, Leung SY, Sohn JJ et al (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425–436PubMedCrossRef Schetter AJ, Leung SY, Sohn JJ et al (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299:425–436PubMedCrossRef
16.
go back to reference Saumet A, Vetter G, Bouttier M et al (2009) Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia. Blood 113:412–421PubMedCrossRef Saumet A, Vetter G, Bouttier M et al (2009) Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia. Blood 113:412–421PubMedCrossRef
17.
go back to reference Visone R, Veronese A, Rassenti LZ et al (2011) miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood 118:3072–3079PubMedCrossRef Visone R, Veronese A, Rassenti LZ et al (2011) miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia. Blood 118:3072–3079PubMedCrossRef
18.
go back to reference Wang LH, Zhou CL, Zhang XW et al (2004) Prevalence and clinical significance of FLT3 internal tandem duplication mutation in acute leukemia. Zhonghua Xue Ye Xue Za Zhi 25:393–396PubMed Wang LH, Zhou CL, Zhang XW et al (2004) Prevalence and clinical significance of FLT3 internal tandem duplication mutation in acute leukemia. Zhonghua Xue Ye Xue Za Zhi 25:393–396PubMed
19.
go back to reference Quentmeier H, Martelli MP, Dirks WG et al (2005) Cell line OCI/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin. Leukemia 19:1760–1767PubMedCrossRef Quentmeier H, Martelli MP, Dirks WG et al (2005) Cell line OCI/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin. Leukemia 19:1760–1767PubMedCrossRef
20.
go back to reference Gu W, Chen Z, Hu S et al (2005) Changes in expression of WT1 isoforms during induced differentiation of the NB4 cell line. Haematologica 90:403–405PubMed Gu W, Chen Z, Hu S et al (2005) Changes in expression of WT1 isoforms during induced differentiation of the NB4 cell line. Haematologica 90:403–405PubMed
21.
go back to reference Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408PubMedCrossRef Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408PubMedCrossRef
22.
go back to reference Cheson BD, Bennett JM, Kopecky KJ et al (2003) Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642–4649PubMedCrossRef Cheson BD, Bennett JM, Kopecky KJ et al (2003) Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21:4642–4649PubMedCrossRef
23.
go back to reference Grimwade D, Walker H, Harrison G et al (2001) The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98:1312–1320PubMedCrossRef Grimwade D, Walker H, Harrison G et al (2001) The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98:1312–1320PubMedCrossRef
24.
go back to reference Valk PJ, Verhaak RG, Beijen MA et al (2004) Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350:1617–1628PubMedCrossRef Valk PJ, Verhaak RG, Beijen MA et al (2004) Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350:1617–1628PubMedCrossRef
25.
go back to reference Ross ME, Mahfouz R, Onciu M et al (2004) Gene expression profiling of pediatric acute myelogenous leukemia. Blood 104:3679–3687PubMedCrossRef Ross ME, Mahfouz R, Onciu M et al (2004) Gene expression profiling of pediatric acute myelogenous leukemia. Blood 104:3679–3687PubMedCrossRef
26.
go back to reference Debernardi S, Skoulakis S, Molloy G et al (2007) MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis. Leukemia 21:912–916PubMed Debernardi S, Skoulakis S, Molloy G et al (2007) MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis. Leukemia 21:912–916PubMed
27.
go back to reference Chen CZ, Li L, Lodish HF et al (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303:83–86PubMedCrossRef Chen CZ, Li L, Lodish HF et al (2004) MicroRNAs modulate hematopoietic lineage differentiation. Science 303:83–86PubMedCrossRef
Metadata
Title
The clinical characteristics and prognostic significance of MN1 gene and MN1-associated microRNA expression in adult patients with de novo acute myeloid leukemia
Authors
Lili Xiang
Man Li
Yan Liu
Jiangnong Cen
Zixing Chen
Xiao Zhen
Xiaobao Xie
Xiangshan Cao
Weiying Gu
Publication date
01-08-2013
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue 8/2013
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-013-1729-x

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