Journal
EMBO JOURNAL
Volume 40, Issue 3, Pages -Publisher
WILEY
DOI: 10.15252/embj.2020105784
Keywords
2p-gain; ALK; ALKAL; MYCN; neuroblastoma
Categories
Funding
- RFI/VR and Science for Life Laboratory, Sweden
- Swedish Cancer Society [CAN18/729, CAN18/718]
- Swedish Childhood Cancer Foundation [PR2015-0096, NCp2015-0061, PR2018-0099, TJ2016-0088, PR2016-2011, TJ2018-0056, PR2017-0110]
- Swedish Research Council [2015-04466, 2017-01324]
- Swedish Foundation for Strategic Research [RB13-0204]
- Goran Gustafsson Foundation
- Ghent University Special Research Fund Starting Grant [BOF.STG.2019.0073.01]
- Goteborgs Lakare Sallskap
- Knut and Alice Wallenberg Foundation [KAW 2018.0057]
- Vinnova [2015-04466] Funding Source: Vinnova
- Swedish Research Council [2017-01324, 2015-04466] Funding Source: Swedish Research Council
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High-risk neuroblastoma, often associated with MYCN oncogene amplification, may benefit from treatment with ALK tyrosine kinase inhibitors targeting activating ALK mutations. Overexpression of ALKAL2 ligand in NB may exacerbate the disease progression, even in the absence of ALK mutations.
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.
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