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Corrigendum
Open Access | 
10.1172/JCI181338
MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma
Yao Zhan, Jun Guo, William Yang, Christophe Goncalves, Tomasz Rzymski, Agnieszka Dreas, Eliza Żyłkiewicz, Maciej Mikulski, Krzysztof Brzózka, Aniela Golas, Yan Kong, Meng Ma, Fan Huang, Bonnie Huor, Qianyu Guo, Sabrina Daniela da Silva, Jose Torres, Yutian Cai, Ivan Topisirovic, Jie Su, Krikor Bijian, Moulay A. Alaoui-Jamali, Sidong Huang, Fabrice Journe, Ghanem E. Ghanem, Wilson H. Miller Jr., and Sonia V. del Rincón
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Published April 15, 2024 - More info
J Clin Invest. 2024;134(8):e181338. https://doi.org/10.1172/JCI181338.
© 2024 Zhan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase–interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring KIT mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for KIT mutations.
Authors
Yao Zhan, Jun Guo, William Yang, Christophe Goncalves, Tomasz Rzymski, Agnieszka Dreas, Eliza Żyłkiewicz, Maciej Mikulski, Krzysztof Brzózka, Aniela Golas, Yan Kong, Meng Ma, Fan Huang, Bonnie Huor, Qianyu Guo, Sabrina Daniela da Silva, Jose Torres, Yutian Cai, Ivan Topisirovic, Jie Su, Krikor Bijian, Moulay A. Alaoui-Jamali, Sidong Huang, Fabrice Journe, Ghanem E. Ghanem, Wilson H. Miller Jr., Sonia V. del Rincón
Original citation: J Clin Invest. 2017;127(11):4179–4192. https://doi.org/10.1172/JCI91258
Citation for this corrigendum: J Clin Invest. 2024;134(8):e181338. https://doi.org/10.1172/JCI181338
The authors recently became aware that in the original Figure 2, A and C, the same eIF4E and GAPDH immunoblots were shown. The legend failed to indicate that these figure panels showed immunoblots from the same lysate, and in Figure 2C, the eIF4E blot for the MM111 D820Y panel was flipped horizontally.
Figure 2MNK1/2 knockdown in HBL cells suppresses cell migration and the expression of cyclin E1 and SNAIL. (A) Western blot analysis of MNK1, p-eIF4E, and eIF4E in HBL or MM111 cells expressing shCTL and shMKNK1+2 (left). RT-qPCR was performed to examine the expression level of MKNK2 mRNA in HBL and MM111 cells expressing shCTL and shMKNK1+2 (right). (B) Cell migration was assessed by Transwell assay in shCTL versus shMKNK1+2 HBL and MM111 cells after 48 hours. Representative images are shown. Scale bars: 200 μm; original magnification, ×10. (A and B) Data represent the mean ± SD, n = 3. **P < 0.01 by 2-tailed Student’s t test. (C) Western blot analysis of MNK1, p-eIF4E, eIF4E, cyclin E1, and SNAIL in HBL and MM111 shCTL and shMKNK1+2 cell lines. (A and C) GAPDH is used as loading control. Panels A and C show Western blot data from lysate derived from the same experiment.
The authors were able to provide immunoblots from the original data and have corrected Figures 2A and 2C to show loading controls for all gels presented in these figure panels and to show immunoblots that were run in parallel within each panel. The authors have also provided the unedited blot and gel images for all immunoblots and gels in the manuscript and supplement. The corrected figure panels and updated figure legend appear below.
The authors regret the errors.
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ISSN: 0021-9738 (print), 1558-8238 (online)