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The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene.
Kelleher, Fergal C McDermott, Ray
Kelleher, Fergal C
McDermott, Ray
Author
Advisors
Editors
Other Contributors
Date
2012-02-01T10:49:46Z
Date Submitted
Keywords
Other Subjects
Subject Mesh
Antineoplastic Agents/therapeutic use
Carcinoma, Non-Small-Cell Lung/genetics/therapy
*Chromosome Aberrations
Chromosomes, Human, Pair 2/*genetics
Drug Synergism
Gene Amplification
Humans
Lung Neoplasms/genetics/therapy
Lymphoma, Large-Cell, Anaplastic/genetics/therapy
Mutation/genetics
Neoplasms/*genetics/therapy
Neuroblastoma/genetics/therapy
Protein-Tyrosine Kinases/antagonists & inhibitors/*genetics
Pyrimidines/therapeutic use
Pyrroles/therapeutic use
Receptor Protein-Tyrosine Kinases
Receptor, IGF Type 1/antagonists & inhibitors
Carcinoma, Non-Small-Cell Lung/genetics/therapy
*Chromosome Aberrations
Chromosomes, Human, Pair 2/*genetics
Drug Synergism
Gene Amplification
Humans
Lung Neoplasms/genetics/therapy
Lymphoma, Large-Cell, Anaplastic/genetics/therapy
Mutation/genetics
Neoplasms/*genetics/therapy
Neuroblastoma/genetics/therapy
Protein-Tyrosine Kinases/antagonists & inhibitors/*genetics
Pyrimidines/therapeutic use
Pyrroles/therapeutic use
Receptor Protein-Tyrosine Kinases
Receptor, IGF Type 1/antagonists & inhibitors
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
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Abstract
The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin's lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered. In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system. Chromosomal abnormalities involving ALK are translocations, amplifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3/4 (TMP3/4), however in IMTs a diversity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic. Point mutations and amplification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic possibilities.
Language
eng
ISSN
1879-0852 (Electronic)
0959-8049 (Linking)
0959-8049 (Linking)
eISSN
ISBN
DOI
10.1016/j.ejca.2010.04.006
PMID
20451371