Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines

  title={Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines},
  author={Willy G. Dirks and Silke F{\"a}hnrich and Yvonne Lis and Elisabeth Becker and Roderick A. F. Macleod and Hans G Drexler},
  journal={International Journal of Cancer},
The initial identification of the ALK gene, expressed as C‐terminal part of the transforming fusion protein NPM‐ALK in the t(2;5)(p23;q35) lymphoma‐associated chromosomal translocation, revealed a novel receptor tyrosine kinase (RTK). In order to expand the knowledge on ALK expression in the human system, we examined a panel of human cell lines for ALK expression and found that transcription is completely repressed in cell lines of entodermal origin (0/21). Furthermore, full length receptor… 
Recombinant expression, characterization, and quantification in human cancer cell lines of the Anaplastic Large-Cell Lymphoma-characteristic NPM-ALK fusion protein
It is estimated that N PM-ALK fusion protein is expressed at substantial levels in both Karpas 299 and SU-DHL-1 cells and compared NPM-ALK/ β-actin ratios determined by ELISA to those independently determined by two-dimensional electrophoresis and showed that the two methods are in good agreement.
Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas.
It is demonstrated that the survival and growth of ALK(+) ALCLs are strictly dependent on ALK activation and signaling, and its inactivation might represent a pivotal approach for the treatment of ALk lymphomas and other ALK-dependent human tumors.
Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells.
Select fused pyrrolocarbazole-derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ ALCL cells in culture.
Anaplastic lymphoma kinase: signalling in development and disease
The role of ALK in development and disease is addressed, implications for the future are discussed and many chromosomal rearrangements leading to enhanced ALK activity are described.
Expression of anaplastic lymphoma kinase in non-Hodgkin's lymphomas and other malignant neoplasms. Biological, diagnostic, and clinical implications.
  • M. Wasik
  • Medicine
    American journal of clinical pathology
  • 2002
Several lines of experimental evidence indicate that the ectopically expressed ALK is oncogenic in ALK+ TCL by being constitutively active owing to autophosphorylation and by stimulating several critical signal transduction pathways involving phospholipase C-gamma, AKT, and STAT3.
Anaplastic lymphoma kinase proteins in growth control and cancer
Reports of ALK expression in a range of carcinoma‐derived cell lines together with its apparent role as a receptor for PTN and MK, both of which have been implicated in tumourigenesis, raise the possibility that ALK‐mediated signalling could play a role in the development and or progression of a number of common solid tumours.
ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer
The biological significance of the ALK receptor in cancer and development is summarized, in perspective with its dependence receptor function, which could have important implications in the therapy of ALK-positive tumors harboring the chimeric or wild type ALK protein.
Development of anaplastic lymphoma kinase (ALK) small‐molecule inhibitors for cancer therapy
A succinct summary of normal ALK biology, the confirmed and putative roles of ALK fusions and the full‐length ALK receptor in the development of human cancers, and efforts to target ALK using small‐molecule kinase inhibitors is provided.
Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy
Normal ALK biology, the confirmed and putative roles of ALK in the development of human cancers and efforts to target ALK using small-molecule kinase inhibitors are summarized.
Oncogenic protein tyrosine kinases
The study of ALK fusion proteins has raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies, given that ALK fusions also occur in the mesenchymal tumor known as inflammatory myofibroblastic tumor (IMT).


Expression of the ALK tyrosine kinase gene in neuroblastoma.
Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system
Molecular cloning of cDNAs for both the human and mouse ALK proteins reveal that ALK is a novel receptor protein-tyrosine kinase having a putative transmembrane domain and an extracellular domain and shows the greatest sequence similarity to LTK (leukocyte tyrosine Kinase) whose biological function is presently unknown.
Expression of the oncogenic NPM-ALK chimeric protein in human lymphoid T-cells inhibits drug-induced, but not Fas-induced apoptosis
Using NPM-ALK mutants, it is demonstrated that inhibition of drug-induced apoptosis requires functional kinase activity, does not involve phospholipase C-γ, essential for N PM-ALK-mediated mitogenicity and appears to be phosphoinositide 3-kinase independent, despite a strong Akt/PKB activation observed in wild type NPM -ALK-expressing cells.
The cytoplasmic truncated receptor tyrosine kinase ALK‐ homodimer immortalizes and cooperates with ras in cellular transformation
  • I. Simonitsch, D. Polgar, C. Cerni
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2001
It is demonstrated by several biological parameters that NPM/ALK is an immortalizing oncogene that provides unlimited, yet normal, growth potential to REC and, with cooperation with a c‐H‐ras onCogene, induces cellular transformation.
Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas
The fact that patients with ALK lymphomas experience significantly better overall survival than ALK− ALCL demonstrates further that analysis of ALK expression has important prognostic implications.
Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis.
The studies demonstrate an alternative mechanism for ALK involvement in the genesis of NHL and suggest that ATic-ALK activation results from ATIC-mediated homodimerization, and expected decreases in ATIC enzymatic function in AT IC-ALK-containing lymphomas may render these tumors more sensitive to antifolate drugs such as methotrexate.
ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK)
Anaplastic Lymphoma Kinase (ALK) was originally identified as a member of the insulin receptor subfamily of receptor tyrosine kinases that acquires transforming capability when truncated and fused to
TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations.
TFG can provide an alternative to NPM as a fusion partner responsible for activation of the ALK and the pathogenesis of ALCL, showing that the new cloned cDNA sequences are translated into chimeric proteins with functional activity.
A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation.
The present cases of ALCL associated with a novel t(1;2)(q25;p23) translocation demonstrate that at least one fusion partner other than NPM can activate the intracytoplasmic domain of the ALK kinase.