This report describes a Drosophila model for cancers related to to the human gene ALK (anaplastic lymphoma kinase), a neuronal receptor tyrosine kinase. ALK has been found to be rearranged, mutated, or amplified in many types of cancer including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer; gene fusions are common. 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. See also the human disease model report 'neuroblastoma, susceptibility to, 3' (NBLST3; FBhh0000712).
Multiple UAS construct of the human Hsap\ALK gene have been introduced into flies, including wild-type, a fusion with human TPM4 (tropomyosin 4) implicated in gastric cancer (see FBhh0001163), and missense variants associated with cancer. 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. In addition to variants implicated in specifically in neuroblastoma (see FBhh0000712), variants identified in anaplastic thyroid tumors have been characterized. Variant(s) implicated in human disease tested (as transgenic human gene, ALK): the variant forms L1198F and G1201E, have been introduced into flies. Additional variants implicated in NBLST3 are described in that report (see FBhh0000712).
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]
See human disease model report 'neuroblastoma, susceptibility to, 3' (FBhh0000712).
Anaplastic thyroid carcinoma (ATC) is an aggressive form of cancer of the thyroid gland. It is one of the fastest growing tumors in humans. Unlike other forms of thyroid cancer (papillary, follicular, medullary, and their variants) it spreads quickly to other organs. Only about 1% of thyroid cancers are of the anaplastic type. [http://www.thyca.org/atc/about-atc/ 2018.01.31]
ALK has been found to be rearranged, mutated, or amplified in many types of cancer including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer; gene fusions are common. [Gene Cards, ALK; 2018.01.29]
ALK encodes a neuronal receptor tyrosine kinase that belongs to the insulin receptor superfamily. [Gene Cards, ALK; 2018.01.29]
See Holla et al., 2017 (pubmed:28050598) for a review of cancers associated with ALK and therapeutic strategies.
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.
