High expression of CPNE3 predicts adverse prognosis in acute myeloid leukemia Huaping Fu,6,10 Jianlin Qiao,4,10 Yifan Pang,8 Keman Xu,9 Lei Zhou,7 Qingyun Wu,4 Zhenyu Li,4 Lin Fu,1,4,5,10 Xiaoyan Ke,1 Kailin Xu4 and Jinlong Shi2,3,5 1 Department of Hematology and Lymphoma Research Center,Third Hospital, Peking University; 2Departments of Biomedical Engineering; 3Departments of Medical Big Data, Chinese PLA General Hospital, Beijing; 4Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou; 5 Department of Hematology, Huaihe Hospital of Henan University, Kaifeng; 6Departments of Nuclear Medicine; 7Department of Hematology, Chinese PLA General Hospital, Beijing, China; 8Department of Medicine, William Beaumont Hospital, Royal Oak; 9Northeastern University, Boston, MA, USA
Key words Acute myeloid leukemia, CPNE3, expression, predicts, prognosis Correspondence Jinlong Shi, Department of BioMedical Engineering, Department of Medical Big Data, Chinese PLA General Hospital, Beijing, China. Tel: +86-10-66936921; Fax: +86-10-66936921; E-mail:
[email protected] and Xiaoyan Ke, Department of Hematology and Lymphoma Research Center, Third Hospital, Peking University, Beijing, China. Tel: +86-10- 82266699; Fax: +86-10-82266699. E-mail:
[email protected] and Kailin Xu, Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Tel: +86-516-85802382; Fax: +86-516-85601527; E-mail:
[email protected] 10
These authors contributed equally to this work.
Funding information This work was supported by grants from the National Natural Science Foundation of China (81500118, 61501519), the China Postdoctoral Science Foundation (through project No. 2016M600443) and the PLAGH Project of Medical Big Data (2016-MBD-025).
CPNE3, a member of a Ca2+-dependent phospholipid-binding protein family, was identified as a ligand of ERBB2 and has a more general role in carcinogenesis. Here, we identified the prognostic significance of CPNE3 expression in acute myeloid leukemia (AML) patients based on two datasets. In the first microarray dataset (n = 272), compared to low CPNE3 expression (CPNE3low), high CPNE3 expression (CPNE3high) was associated with adverse overall survival (OS, P < 0.001) and event-free survival (EFS, P < 0.001). In the second independent group of AML patients (TCGA dataset, n = 179), CPNE3high was also associated with adverse OS and EFS (OS, P = 0.01; EFS, P = 0.036). Notably, among CPNE3high patients, those received allogenic hematopoietic cell transplantation (HCT) had longer OS and EFS than those with chemotherapy alone (allogeneic HCT, n = 40 vs chemotherapy, n = 46), but treatment modules played an insignificant role in the survival of CPNE3low patients (allogeneic HCT, n = 32 vs chemotherapy, n = 54). These results indicated that CPNE3high is an independent, adverse prognostic factor in AML and might guide treatment decisions towards allogeneic HCT. To understand its inherent mechanisms, we investigated genome-wide gene/microRNA expression signatures and cell signaling pathways associated with CPNE3 expression. In conclusion, CPNE3high is an adverse prognostic biomarker for AML. Its effect may be attributed to the distinctive genome-wide gene/ microRNA expression and related cell signaling pathways.
Received May 4, 2017; Revised June 27, 2017; Accepted June 28, 2017 Cancer Sci (2017) doi: 10.1111/cas.13311
A
cute myeloid leukemias (AML), which harbor mutations and aberrantly expressed genes,(1) microRNA,(2) lncRNA(3) and changes in DNA methylation that are potential prognostic markers,(4) are a group of myeloid malignancies with remarkably heterogeneous outcomes.(5) The need to find effective prognostic biomarkers is pressing and has become a research hotspot. ERBB signaling pathway, a paradigm for oncogene addiction,(6) promotes AML growth.(7) ERBB2, which can promote breast cancer growth, metastasis and drug-resistance, is an important factor of ERBB signaling pathway.(8) CPNE3, as a phosphoprotein with associated kinase activity(9) and a novel metastasis-promoting gene in non-small-cell lung cancer,(10) has been identified as a ligand of ERBB2 and has a more © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attrib ution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
general role in carcinogenesis.(11) Jun activation domain-binding protein 1 (Jab1) can enhance the ERBB2-binding ability of CPNE3, further activating the ERBB signaling pathways involved in breast cancer cell pathogenesis.(12) According to the role of ERBB2 in the pathogenesis of carcinogenesis, it was speculated that the expression of CPNE3 might be related to prognosis in patients with AML. Here, we demonstrate CPNE3high as an adverse prognostic biomarker for AML based on analysis of two separate datasets. We also explore the distinctive gene/microRNA patterns and cell signaling pathways associated with CPNE3 expression in AML patients.
Cancer Sci | 2017
© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
41 16–59 55 41.74 0.43–210.9 27.12 0.03–210.9 6 (4.4) 45 (33.1) 44 (32.3) 13 (9.6) 21 (15.4) 2 (1.5) 5 (3.7) 25 (18.4) 4 (2.9) 57 (41.9) 50 (36.8) 16 (11.8) 5 (3.7) 20 (14.7) 111 (81.6) 11 (8.1) 12 (8.9) 17 (12.5) 12 (8.8) 1 (0.7)
15.7 0.07–214.5
8.81 0.03–214.5
5 (3.7) 21 (15.4) 17 (12.5) 43 (31.6) 41 (30.2) 0 9 (6.6)
20 (14.7) 2 (1.5) 72 (52.9) 42 (30.9) 11 (8.1)
3 (2.2) 1 (0.7) 132 (97.1) 20 (14.7) 12 (8.9) 7 (5.1) 14 (10.3) 3 (2.2)
CPNE3low (n = 136)
47 15–59 67
CPNE3high (n = 136)
AML
0.72
