This report describes a Drosophila model for neuroblastoma, susceptibility to, 3 (NBLST3). The human gene implicated in this disease in ALK (anaplastic lymphoma kinase), a neuronal receptor tyrosine kinase. There is a single orthologous gene in Drosophila, Dmel\Alk, for which for which loss-of-function alleles, RNAi targeting constructs, and an allele caused by insertional mutagenesis have been generated. Dmel\Alk is also orthologous to a second gene in human, LTK; however, LTK is a shorter protein that lacks a protein domain found in ALK and Dmel\Alk. The human ALK gene is implicated in a number of other cancers; see the human disease model report 'cancer, multiple, ALK-related' (FBhh0000713).
Multiple UAS construct of the human Hsap\ALK gene have been introduced into flies, including wild-type and variants associated with NBLST3. The Drosophila ALK ligand, encoded by jeb, is unable to activate either human or mouse ALK orthologs; however, co-expression with the human ALK ligands, Hsap\ALKAL1 or Hsap\ALKAL2, results in robust activation of the human receptor in the Drosophila eye. Severity of the resulting eye phenotypes can be used to categorize variants as GOF, LOF (and to what degree), whether ligand dependent or ligand independent. Variant(s) implicated in human disease tested (as transgenic human gene, ALK): the variant forms IL, F1174S, A1234T, I1250T, R1275Q, and Y1278S have been introduced into flies. In some cases, response to pharmacological intervention has been tested. A disease-implicated variant has also been constructed in a zebrafish ortholog of both human ALK and human LTK, Drer\ltkmne.UAS, and has been introduced into flies; this construct carries a modification analogous to variant form F1174 of the human gene.
Animals homozygous for loss-of-function mutations of Dmel\Alk typically die in the late embryonic or early larval stages. Less severe and conditional alleles result in neurophysiology and behavioral defects. A small number of genetic and physical interactions have been described for Dmel\Alk; see below and in the Alk gene report.
[updated Jan. 2020 by FlyBase; FBrf0222196]
[NEUROBLASTOMA, SUSCEPTIBILITY TO, 3; NBLST3](https://omim.org/entry/613014)
[ALK RECEPTOR TYROSINE KINASE; ALK](https://omim.org/entry/105590)
Neuroblastoma occurs most often in children before age 5 and rarely occurs in adults. [Genetics Home Reference, Neuroblastoma; 2018.01.29]
Neuroblastoma (NB) is the most common solid childhood tumor outside the brain and causes 15% of childhood cancer-related mortality. The main drivers of NB formation are neural crest cell-derived sympathoadrenal cells that undergo abnormal genetic arrangements. [Valter et al., 2018; 29371588]
Neuroblastoma occurs when neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the neuroblasts of the adrenal gland located above each kidney; other common sites for the original tumors to form include neuroblasts in the abdomen, chest, neck, or pelvis. Neuroblastoma can metastasize to other parts of the body such as the bones, liver, or skin. Individuals with neuroblastoma may develop general signs and symptoms such as irritability, fever, fatigue, pain, loss of appetite, weight loss, or diarrhea. More specific signs and symptoms depend on the location of the tumor and where it has spread. [Genetics Home Reference, Neuroblastoma; 2018.01.29]
ALK-related neuroblastic tumor susceptibility results from heterozygosity for a germline ALK activating pathogenic variant in the tyrosine kinase domain that predisposes to neuroblastic tumors. [Gene_reviews, ALK-Related Neuroblastic Tumor Susceptibility; 2018.01.29]
Susceptibility to neuroblastoma-3 (NBLST3) is conferred by germline or somatic mutations in the ALK gene. [from MIM:613014; 2018.01.26]
ALK encodes a neuronal receptor tyrosine kinase that belongs to the insulin receptor superfamily. [Gene Cards, ALK; 2018.01.29]
Many to one: 2 human to 1 Drosophila; the second human gene is LTK. LTK is a shorter protein, lacking the meprin domains found in ALK and Dmel\Alk.
