J Cancer 2019; 10(26):6570-6583. doi:10.7150/jca.30223

Research Paper

Up-regulation of EMT-related gene VCAN by NPM1 mutant-driven TGF-β/cPML signalling promotes leukemia cell invasion

Liyuan Yang1*, Lu Wang1*, Zailin Yang2, Hongjun Jin1, Qin Zou1, Qian Zhan3, Yuting Tang1, Yao Tao1, Li Lei1, Yipei Jing1, Xueke Jiang1, Ling Zhang1✉

1. Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
2. Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China.
3. The Center for Clinical Molecular Medical detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
* These authors contributed equally to this article.

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Citation:
Yang L, Wang L, Yang Z, Jin H, Zou Q, Zhan Q, Tang Y, Tao Y, Lei L, Jing Y, Jiang X, Zhang L. Up-regulation of EMT-related gene VCAN by NPM1 mutant-driven TGF-β/cPML signalling promotes leukemia cell invasion. J Cancer 2019; 10(26):6570-6583. doi:10.7150/jca.30223. Available from http://www.jcancer.org/v10p6570.htm

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Abstract

Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) is acknowledged as a distinct leukemia entity in the 2016 updated World Health Organization (WHO) classification. NPM1-mutated AML patients are correlated with higher extramedullary involvement. Epithelial-mesenchymal transition (EMT) is one of the key steps which cause distant metastasis in tumor. However, whether EMT-related programs contribute to cell invasion in NPM1-mutated AML remains unclear. In this study, we identified the EMT-related gene versican (VCAN) in NPM1-mutated AML across three patient datasets. Further experiments validated the elevated VCAN expression in NPM1-mutated AML primary blasts and OCI-AML3 cells with NPM1 mutation. Mechanistic studies revealed that increased VCAN expression was at least partially regulated by NPM1 mutant via TGF-β/cPML/Smad signalling. Functional evaluations showed that silencing VCAN by shRNA significantly suppressed cell migration and invasion capacity, whereas increased VCAN by overexpressing NPM1-mA enhanced migration and invasion ability of leukemia cells. Finally, we found that high expression of VCAN was associated with poor prognosis in AML patients. These findings provide insights into the involvement of EMT-related gene VCAN in the pathogenesis of NPM1-mutated leukemia, which suggests that VCAN is an attractive target for novel diagnostic and therapeutic strategies in NPM1-mutated AML.

Keywords: acute myeloid leukemia, nucleophosmin, gene mutation, epithelial-mesenchymal transition, versican, cell invasion