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Arsenic trioxide degrades NPM-ALK fusion protein and inhibits growth of ALK-positive anaplastic large cell lymphoma

Leukemia volume 31, pages 522–526 (2017)Cite this article

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Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma. Depending on the presence or absence of chromosomal rearrangements involving anaplastic lymphoma kinase (ALK) gene on 2p23, systemic ALCL is classified into ALK-positive and ALK-negative ALCL. Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like regimens are commonly used for the treatment of ALCL. Although ALK-positive ALCL is generally associated with better response to treatment and overall survival than ALK-negative ALCL,1 patients with relapsed or refractory ALK-positive ALCL have poorer outcome with short survival.2 Optimal therapies for these patients remain undefined. The chromosomal translocation t(2;5)(p23;q35), found in 40% of ALCL and over 80% of ALK-positive ALCL, results in the formation of the nucleophosmin (NPM)-ALK fusion gene.3, 4 The molecular consequence is aberrant expression of the chimeric fusion oncoprotein NPM-ALK,5 leading to dysregulated ALK kinase activity otherwise absent in normal mature T-lymphocytes. Anaplastic lymphoma kinase activation has been demonstrated to have a central role in lymphomagenesis, maintaining the proliferation of ALK-positive ALCL cells.6 The JAK/STAT signaling pathway is one of the most characterized downstream pathways and is indispensable for ALK-mediated lymphomagenesis.7 In addition, activation of the PI3K/AKT pathway has also been demonstrated as an important event in ALK-induced malignant transformation.8

Arsenic trioxide (ATO) is a highly effective therapeutic agent for acute promyelocytic leukemia (APL) through inducing degradation of its hallmark fusion oncoprotein PML-RARA (promyelocytic leukemia-retinoic acid receptor A).9, 10 Recent studies have shown that NPMc+, a mutant NPM protein expressed in acute myeloid leukemia (AML) with NPM gene mutations, is also targeted by ATO for degradation.11, 12 On the basis of these findings, we hypothesized that ATO might also target the NPM-ALK fusion protein, thereby achieving anti-lymphoma effect in ALK-positive ALCL.

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Acknowledgements

The project was partly supported by a General Research Fund (HKU779813), Research Grant Council, Hong Kong. The authors thank Dr Timothy Cheng for technical advice, Ka-Wai Leong for assistance in statistical analysis and KS Cheung for animal husbandry.

Author contributions

WP designed and performed the experiments, and wrote and approved the manuscript. DC and LMY performed the experiments and approved the manuscript. YLK conceived the study and approved the manuscript. ET conceived the study, designed the experiments, and wrote and approved the manuscript.

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  1. Division of Haematology, Department of Medicine, The University of Hong Kong, Hong Kong, China

    W Piao, D Chau, L M Yue, Y-L Kwong & E Tse

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  1. W Piao
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Correspondence to E Tse.

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Competing interests

The University of Hong Kong holds the patent for the use of oral formulation of arsenic trioxide in USA and Japan. DC, YLK and ET are employees of the University of Hong Kong.

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Piao, W., Chau, D., Yue, L. et al. Arsenic trioxide degrades NPM-ALK fusion protein and inhibits growth of ALK-positive anaplastic large cell lymphoma. Leukemia 31, 522–526 (2017). https://doi.org/10.1038/leu.2016.311

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