TitleInhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas.
Publication TypeJournal Article
Year of Publication2011
AuthorsCerchietti, Leandro, Damm-Welk Christine, Vater Inga, Klapper Wolfram, Harder Lana, Pott Christiane, Yang Shao Ning, Reiter Alfred, Siebert Reiner, Melnick Ari, and Woessmann Willi
JournalPLoS One
Volume6
Issue4
Paginatione18436
Date Published2011 Apr 08
ISSN1932-6203
KeywordsAnaplastic Lymphoma Kinase, Animals, Base Sequence, Cell Death, Cell Line, Tumor, Cell Proliferation, Humans, Immunocompromised Host, Immunophenotyping, Lymphoma, Large B-Cell, Diffuse, Mice, Mice, SCID, Molecular Sequence Data, Oncogene Proteins, Fusion, Protein Kinase Inhibitors, Pyrimidines, Receptor Protein-Tyrosine Kinases, Remission Induction, Signal Transduction, Xenograft Model Antitumor Assays
Abstract

<p>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.</p>

DOI10.1371/journal.pone.0018436
Alternate JournalPLoS One
PubMed ID21494621
PubMed Central IDPMC3072987