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Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions

Authors: Lin Fu, Huaping Fu, Qingyun Wu, Yifan Pang, Keman Xu, Lei Zhou, Jianlin Qiao, Xiaoyan Ke, Kailin Xu, Jinlong Shi

Published in: Journal of Translational Medicine | Issue 1/2017

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Abstract

Background

ETS2 is a downstream effector of the RAS/RAF/ERK pathway, which plays a critical role in the development of malignant tumor. However, the clinical impact of ETS2 expression in AML remains unknown.

Methods

In this study, we evaluated the prognostic significance of ETS2 expression using two relatively large cohorts of AML patients.

Results

In the first cohort, compared to low expression of ETS2 (ETS2 low), high expression of ETS2 (ETS2 high) showed significant shorter OS, EFS and RFS in the current treatments including the allogeneic HCT group (n = 72) and the chemotherapy group (n = 100). Notably, among ETS2 high patients, those received allogeneic HCT had longer OS, EFS and RFS than those with chemotherapy alone (allogeneic HCT, n = 39 vs. chemotherapy, n = 47), but treatment modules play insignificant role in the survival of ETS2 low patients (allogeneic HCT, n = 33 vs. chemotherapy, n = 53). Moreover, gene/microRNA expression data provides insights into the biological changes associated with varying ETS2 expression levels in AML. The prognostic value of ETS2 was further validated in the second AML cohort (n = 329).

Conclusions

Our results indicate that ETS2 high is a poor prognostic factor in AML and may guide treatment decisions towards allogeneic HCT.
Appendix
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Literature
1.
go back to reference Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–52.CrossRefPubMed Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–52.CrossRefPubMed
3.
go back to reference Marcucci G, et al. Clinical role of microRNAs in cytogenetically normal acute myeloid leukemia: miR-155 upregulation independently identifies high-risk patients. J Clin Oncol. 2013;31(17):2086–93.CrossRefPubMedPubMedCentral Marcucci G, et al. Clinical role of microRNAs in cytogenetically normal acute myeloid leukemia: miR-155 upregulation independently identifies high-risk patients. J Clin Oncol. 2013;31(17):2086–93.CrossRefPubMedPubMedCentral
4.
go back to reference Xu LH, et al. Overexpressed miR-155 is associated with initial presentation and poor outcome in Chinese pediatric acute myeloid leukemia. Eur Rev Med Pharmacol Sci. 2015;19(24):4841–50.PubMed Xu LH, et al. Overexpressed miR-155 is associated with initial presentation and poor outcome in Chinese pediatric acute myeloid leukemia. Eur Rev Med Pharmacol Sci. 2015;19(24):4841–50.PubMed
5.
go back to reference Marcucci G, et al. Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a cancer and leukemia group B study. J Clin Oncol. 2005;23(36):9234–42.CrossRefPubMed Marcucci G, et al. Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a cancer and leukemia group B study. J Clin Oncol. 2005;23(36):9234–42.CrossRefPubMed
6.
go back to reference Schwind S, et al. BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. Blood. 2010;116(25):5660–9.CrossRefPubMedPubMedCentral Schwind S, et al. BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. Blood. 2010;116(25):5660–9.CrossRefPubMedPubMedCentral
7.
go back to reference Langer C, et al. 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. 2009;27(19):3198–204.CrossRefPubMedPubMedCentral Langer C, et al. 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. 2009;27(19):3198–204.CrossRefPubMedPubMedCentral
8.
go back to reference Wasylyk B, Hagman J, Gutierrez-Hartmann A. Ets transcription factors: nuclear effectors of the Ras-MAP-kinase signaling pathway. Trends Biochem Sci. 1998;23(6):213–6.CrossRefPubMed Wasylyk B, Hagman J, Gutierrez-Hartmann A. Ets transcription factors: nuclear effectors of the Ras-MAP-kinase signaling pathway. Trends Biochem Sci. 1998;23(6):213–6.CrossRefPubMed
9.
go back to reference Baldus CD, et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA. 2004;101(11):3915–20.CrossRefPubMedPubMedCentral Baldus CD, et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA. 2004;101(11):3915–20.CrossRefPubMedPubMedCentral
10.
go back to reference Ge Y, et al. The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia. 2008;22(3):521–9.CrossRefPubMed Ge Y, et al. The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia. 2008;22(3):521–9.CrossRefPubMed
11.
go back to reference Santoro A, et al. Amplification of ETS2 oncogene in acute nonlymphoblastic leukemia with t(6;21;18). Cancer Genet Cytogenet. 1992;58(1):71–5.CrossRefPubMed Santoro A, et al. Amplification of ETS2 oncogene in acute nonlymphoblastic leukemia with t(6;21;18). Cancer Genet Cytogenet. 1992;58(1):71–5.CrossRefPubMed
12.
go back to reference Kabbout M, et al. ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer. Clin Cancer Res. 2013;19(13):3383–95.CrossRefPubMed Kabbout M, et al. ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer. Clin Cancer Res. 2013;19(13):3383–95.CrossRefPubMed
13.
go back to reference The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.CrossRefPubMedCentral The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.CrossRefPubMedCentral
14.
go back to reference Verhaak RG, et al. Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica. 2009;94(1):131–4.CrossRefPubMed Verhaak RG, et al. Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica. 2009;94(1):131–4.CrossRefPubMed
15.
go back to reference Laszlo GS, et al. High expression of suppressor of cytokine signaling-2 predicts poor outcome in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Leuk Lymphoma. 2014;55(12):2817–21.CrossRefPubMedPubMedCentral Laszlo GS, et al. High expression of suppressor of cytokine signaling-2 predicts poor outcome in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Leuk Lymphoma. 2014;55(12):2817–21.CrossRefPubMedPubMedCentral
16.
go back to reference van der Reijden BA, Monteferrario D, Jansen JH, Huls G. High expression of transcription factor 4 (TCF4) is an independent adverse prognostic factor in acute myeloid leukemia that could guide treatment decisions. Haematologica. 2014;99(12):e257–9.CrossRefPubMedPubMedCentral van der Reijden BA, Monteferrario D, Jansen JH, Huls G. High expression of transcription factor 4 (TCF4) is an independent adverse prognostic factor in acute myeloid leukemia that could guide treatment decisions. Haematologica. 2014;99(12):e257–9.CrossRefPubMedPubMedCentral
17.
go back to reference Fu L, et al. High expression of MAP7 predicts adverse prognosis in young patients with cytogenetically normal acute myeloid leukemia. Sci Rep. 2016;6:34546.CrossRefPubMedPubMedCentral Fu L, et al. High expression of MAP7 predicts adverse prognosis in young patients with cytogenetically normal acute myeloid leukemia. Sci Rep. 2016;6:34546.CrossRefPubMedPubMedCentral
18.
go back to reference Zhou JD, et al. Clinical significance of up-regulated ID1 expression in Chinese de novo acute myeloid leukemia. Int J Clin Exp Pathol. 2015;8(5):5336–44.PubMedPubMedCentral Zhou JD, et al. Clinical significance of up-regulated ID1 expression in Chinese de novo acute myeloid leukemia. Int J Clin Exp Pathol. 2015;8(5):5336–44.PubMedPubMedCentral
19.
go back to reference Byers RJ, et al. MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia. Blood. 2011;118(10):2857–67.CrossRefPubMed Byers RJ, et al. MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia. Blood. 2011;118(10):2857–67.CrossRefPubMed
20.
go back to reference Roman-Gomez J, et al. Cadherin-13, a mediator of calcium-dependent cell–cell adhesion, is silenced by methylation in chronic myeloid leukemia and correlates with pretreatment risk profile and cytogenetic response to interferon alfa. J Clin Oncol. 2003;21(8):1472–9.CrossRefPubMed Roman-Gomez J, et al. Cadherin-13, a mediator of calcium-dependent cell–cell adhesion, is silenced by methylation in chronic myeloid leukemia and correlates with pretreatment risk profile and cytogenetic response to interferon alfa. J Clin Oncol. 2003;21(8):1472–9.CrossRefPubMed
21.
go back to reference Zhou J, et al. Synergistic antitumor activity of triple-regulated oncolytic adenovirus with VSTM1 and daunorubicin in leukemic cells. Apoptosis. 2016;21(10):1179–90.CrossRefPubMed Zhou J, et al. Synergistic antitumor activity of triple-regulated oncolytic adenovirus with VSTM1 and daunorubicin in leukemic cells. Apoptosis. 2016;21(10):1179–90.CrossRefPubMed
23.
go back to reference Vecchione A, et al. Fez1/Lzts1 absence impairs Cdk1/Cdc25C interaction during mitosis and predisposes mice to cancer development. Cancer Cell. 2007;11(3):275–89.CrossRefPubMedPubMedCentral Vecchione A, et al. Fez1/Lzts1 absence impairs Cdk1/Cdc25C interaction during mitosis and predisposes mice to cancer development. Cancer Cell. 2007;11(3):275–89.CrossRefPubMedPubMedCentral
26.
go back to reference Zhi Y, et al. Serum level of miR-10-5p as a prognostic biomarker for acute myeloid leukemia. Int J Hematol. 2015;102(3):296–303.CrossRefPubMed Zhi Y, et al. Serum level of miR-10-5p as a prognostic biomarker for acute myeloid leukemia. Int J Hematol. 2015;102(3):296–303.CrossRefPubMed
27.
go back to reference Saleh LM, et al. Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia. Leukemia. 2017;31:340–49.CrossRefPubMed Saleh LM, et al. Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia. Leukemia. 2017;31:340–49.CrossRefPubMed
28.
29.
go back to reference Gentner B, et al. MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia. Exp Hematol. 2015;43(10):858–868.e7.CrossRefPubMedPubMedCentral Gentner B, et al. MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia. Exp Hematol. 2015;43(10):858–868.e7.CrossRefPubMedPubMedCentral
30.
go back to reference Wang XS, et al. MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. Blood. 2012;119(21):4992–5004.CrossRefPubMed Wang XS, et al. MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. Blood. 2012;119(21):4992–5004.CrossRefPubMed
31.
go back to reference Hershkovitz-Rokah O, et al. MiR-30e induces apoptosis and sensitizes K562 cells to imatinib treatment via regulation of the BCR-ABL protein. Cancer Lett. 2015;356(2 Pt B):597–605.CrossRefPubMed Hershkovitz-Rokah O, et al. MiR-30e induces apoptosis and sensitizes K562 cells to imatinib treatment via regulation of the BCR-ABL protein. Cancer Lett. 2015;356(2 Pt B):597–605.CrossRefPubMed
32.
go back to reference Yang Y, et al. miR-137 and miR-197 induce apoptosis and suppress tumorigenicity by targeting MCL-1 in multiple myeloma. Clin Cancer Res. 2015;21(10):2399–411.CrossRefPubMed Yang Y, et al. miR-137 and miR-197 induce apoptosis and suppress tumorigenicity by targeting MCL-1 in multiple myeloma. Clin Cancer Res. 2015;21(10):2399–411.CrossRefPubMed
33.
go back to reference Nibourel O, et al. Copy-number analysis identified new prognostic marker in acute myeloid leukemia. Leukemia. 2017;31(3):555–64.CrossRefPubMed Nibourel O, et al. Copy-number analysis identified new prognostic marker in acute myeloid leukemia. Leukemia. 2017;31(3):555–64.CrossRefPubMed
34.
go back to reference Corces MR, et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat Genet. 2016;48(10):1193–203.CrossRefPubMedPubMedCentral Corces MR, et al. Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat Genet. 2016;48(10):1193–203.CrossRefPubMedPubMedCentral
35.
go back to reference Kadia TM, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016;122(22):3484-91.CrossRef Kadia TM, et al. TP53 mutations in newly diagnosed acute myeloid leukemia: clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016;122(22):3484-91.CrossRef
37.
go back to reference Quinn SR, et al. The role of Ets2 transcription factor in the induction of microRNA-155 (miR-155) by lipopolysaccharide and its targeting by interleukin-10. J Biol Chem. 2014;289(7):4316–25.CrossRefPubMed Quinn SR, et al. The role of Ets2 transcription factor in the induction of microRNA-155 (miR-155) by lipopolysaccharide and its targeting by interleukin-10. J Biol Chem. 2014;289(7):4316–25.CrossRefPubMed
Metadata
Title
High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions
Authors
Lin Fu
Huaping Fu
Qingyun Wu
Yifan Pang
Keman Xu
Lei Zhou
Jianlin Qiao
Xiaoyan Ke
Kailin Xu
Jinlong Shi
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-017-1260-2

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