ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation
Open Access
- 1 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 40 (3), e105784
- https://doi.org/10.15252/embj.2020105784
Abstract
High-risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of high-risk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. 8-10% of primary NB patients are ALK-positive, a figure that increases in the relapsed population. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the "2p-gain" region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, although one of the first oncogenes described was v-sis that shares > 90% homology with PDGF. Therefore, we tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI-sensitive NB in the absence of ALK mutation, suggesting that additional NB patients, such as those exhibiting 2p-gain, may benefit from ALK TKI-based therapeutic intervention.Funding Information
- Cancerfonden (CAN18/729, CAN18/718)
- Barncancerfonden (PR2015‐0096, PR2017‐0110, PR2018‐0099, NCp2015‐0061, TJ2016‐0088, PR2016‐2011, TJ2018‐0056)
- Stiftelsen för Strategisk Forskning (RB13‐0204)
- Vetenskapsrådet (2017‐01324, 2015‐04466)
- Knut och Alice Wallenbergs Stiftelse (KAW 2018.0057)
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