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ALK ligand ALKAL2 potentiates MYCN‐driven neuroblastoma in the absence of ALK mutation
Author(s) -
Borenäs Marcus,
Umapathy Ganesh,
Lai WeiYun,
Lind Dan E,
Witek Barbara,
Guan Jikui,
MendozaGarcia Patricia,
Masudi Tafheem,
Claeys Arne,
Chuang TzuPo,
El Wakil Abeer,
Arefin Badrul,
Fransson Susanne,
Koster Jan,
Johansson Mathias,
Gaarder Jennie,
Van den Eynden Jimmy,
Hallberg Bengt,
Palmer Ruth H
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020105784
Subject(s) - anaplastic lymphoma kinase , neuroblastoma , alk inhibitor , biology , cancer research , crizotinib , tyrosine kinase , mutation , oncogene , n myc , genetics , microbiology and biotechnology , cancer , medicine , gene , signal transduction , lung cancer , cell culture , ganglioneuroma , malignant pleural effusion , cell cycle
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.