EMBO J. 2021 Jan 7;e105784. doi: 10.15252/embj.2020105784. Online ahead of print.
ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Department of Molecular Biology, Umeå University, Umeå, Sweden. Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China. Department of Human Structure and Repair, Anatomy and Embryology Unit, Ghent University, Ghent, Belgium. Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Clinical Genomics, Science for life laboratory, University of Gothenburg, Gothenburg, Sweden.
Service type: Knock-in mice
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. Keywords: 2p-gain; ALK; ALKAL; MYCN; neuroblastoma.View Publication