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Prognostic significance of combined MN1, ERG, BAALC, and EVI1 (MEBE) expression in patients with myelodysplastic syndromes

Abstract

Overexpression of MN1, ERG, BAALC, and EVI1 (MEBE) genes in cytogenetically normal acute myeloid leukemia (AML) patients is associated with poor prognosis, but their prognostic effect in patients with myelodysplastic syndromes (MDS) has not been studied systematically. Expression data of the four genes from 140 MDS patients were combined in an additive score, which was validated in an independent patient cohort of 110 MDS patients. A high MEBE score, defined as high expression of at least two of the four genes, predicted a significantly shorter overall survival (OS) (HR 2.29, 95 % CI 1.3–4.09, P = .005) and time to AML progression (HR 4.83, 95 % CI 2.01–11.57, P < .001) compared to a low MEBE score in multivariate analysis independent of karyotype, percentage of bone marrow blasts, transfusion dependence, ASXL1, and IDH1 mutation status. In a validation cohort of 110 MDS patients, a high MEBE score predicted shorter OS (HR 1.77; 95 % CI 1.04–3.0, P = .034) and time to AML progression (HR 3.0, 95 % CI 1.17–7.65, P = .022). A high MEBE expression score is an unfavorable prognostic marker in MDS and is associated with an increased risk for progression to AML. Expression of the MEBE genes is regulated by FLI1 and c-MYC, which are potential upstream targets of the MEBE signature.

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Acknowledgments

We thank all patients, contributing doctors, and Tayside Cancer Tissue Bank for their participation in this study. We thank Kerstin Görlich, Elvira Lux, Sylvia Horter, Susanne Luther, Jana König, and Maren Herten for their excellent support in sample and data acquisition. This study was supported by the Deutsche Krebshilfe e.V (grant no. 109003), grant no. DJCLS R 10/22 from the Deutsche-José-Carreras Leukämie-Stiftung e.V, grant no. M 47.1 from the H. W. & J. Hector Stiftung, the Dieter-Schlag-Stiftung grant from 2011, the German Federal Ministry of Education and Research grant 01EO0802, DFG grants HE 5240/4-1 and TH 1779/1-1, and HiLF grant from Hannover Medical School awarded to FT.

Conflict of interest

T.H. owns and is employed by the Munich Leukemia Laboratory GmbH. The other authors indicated no potential conflicts of interest.

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Authors

Corresponding author

Correspondence to Michael Heuser.

Additional information

Arnold Ganser and Michael Heuser contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Table S1

Comparison of clinical and molecular characteristics of MDS patients with low or high MN1 expression. (DOC 102 kb)

Table S2

Comparison of clinical and molecular characteristics of MDS patients with low or high ERG expression. (DOC 101 kb)

Table S3

Comparison of clinical and molecular characteristics of MDS patients with low or high BAALC expression. (DOC 101 kb)

Table S4

Comparison of clinical and molecular characteristics of MDS patients with low or high EVI1 expression. (DOC 102 kb)

Table S5

Correlation between MN1, ERG, BAALC and EVI1 expression in MDS patients. (DOC 43 kb)

Table S6

List of gene sets enriched or depleted in MDS patients with high MEBE expression score. (DOC 126 kb)

Table S7

Primers used to quantify expression of mouse Mn1, Erg, Baalc, and Evi1. (DOC 42 kb)

Supplemental Figure S1

Prognostic impact of individual gene expression markers in MDS patients in the validation cohort. Kaplan-Meier curves for overall survival and time to AMLtransformation are shown. (A) Overall survival in MDS patients with low or high MN1 expression. (B) Time to AML transformation in MDS patients with low or high MN1 expression. (C) Overall survival in MDS patients with low or high ERG expression. (D) Time to AML transformation in MDS patients with low or high ERG expression. (E) Overall survival in MDS patients with low or high BAALC expression. (F) Time to AML transformation in MDS patients with low or high BAALC expression. (G) Overall survival in MDS patients with high EVI1 vs. low EVI1 expression (see Materials and Methods for definition of high vs. low expression). Time to AML transformation in MDS patients with high EVI1 vs. low EVI1 expression (see Materials and Methods for definition of high vs. low expression). (DOC 205 kb)

Supplemental Figure S2

Prognostic impact of the MEBE expression score in younger and older MDS patients. (A) Overall survival in MDS patients younger than 66 years of age with low or high MEBE score. (B) Time to AML transformation in MDS patients younger than 66 years of age with low or high MEBE score. (C) Overall survival in MDS patients 66 years of age or older with low or high MEBE score. Time to AML transformation in MDS patients 66 years of age or older with low) or high MEBE score. (DOC 124 kb)

Supplemental Figure S3

Prognostic impact of the MEBE expression score determined from bone marrow or peripheral blood in MDS patients. (A) Only bone marrow (BM) samples considered: Overall survival in MDS patients with low or high MEBE score. (B) Only bone marrow samples (BM) considered: Time to AML transformation in MDS patients with low or high MEBE score. (C) Only peripheral blood samples considered: Overall survival in MDS patients with low or high MEBE score. (D) Only peripheral blood samples considered: Time to AML transformation in MDS patients with low or high MEBE score (DOC 122 kb)

Supplemental Figure S4

Prognostic impact of the MEBE expression score in MDS patients with 10-19 percent bone marrow blasts. (A) Overall survival in MDS patients with low or high MEBE score in patients with 10-19 percent bone marrow blasts. (B) Time to AML transformation in MDS patients with low or high MEBE score in patients with 10-19 percent bone marrow blasts. (DOC 70 kb)

Supplemental Figure S5

Correlation of expression classes (high or low) of individual gene expression markers of the MEBE score. Each row represents one patient. Yellow, low expression or low MEBE score. Blue, high expression or high MEBE score. (DOC 142 kb)

Supplemental Figure S6

Effect of constitutive expression of Fli1 and c-Myc on expression levels of Mn1, Erg, Baalc, and Evi1 in mouse bone marrow cells. Fli1, c-Myc, or a control vector was stably expressed in mouse bone marrow cells. Transduced cells were sorted and harvested after 7 days, and cDNA was prepared for expression analysis. Abl was used as a housekeeping gene, and expression ratios of transgene expressing cells vs. control vector-transduced cells are shown (n=3, mean ± SD). Expression of Baalc could be detected by nested PCR only. (DOC 97 kb)

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Thol, F., Yun, H., Sonntag, AK. et al. Prognostic significance of combined MN1, ERG, BAALC, and EVI1 (MEBE) expression in patients with myelodysplastic syndromes. Ann Hematol 91, 1221–1233 (2012). https://doi.org/10.1007/s00277-012-1457-7

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Keywords

  • MDS
  • Prognosis
  • Gene expression
  • Score
  • Splicing