Abstract
ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anaplastic Lymphoma Kinase
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Animals
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Base Sequence
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Cell Death / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Humans
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Immunocompromised Host
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Immunophenotyping
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Lymphoma, Large B-Cell, Diffuse / drug therapy*
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Lymphoma, Large B-Cell, Diffuse / enzymology*
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / pathology
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Mice
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Mice, SCID
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Molecular Sequence Data
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Oncogene Proteins, Fusion / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Remission Induction
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Signal Transduction / drug effects
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Xenograft Model Antitumor Assays
Substances
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NVP-TAE684
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Oncogene Proteins, Fusion
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Protein Kinase Inhibitors
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Pyrimidines
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oncoprotein CLTCL-ALK
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases