A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation Academic Article uri icon

Overview

MeSH Major

  • Drug Resistance, Neoplasm
  • Lymphoma, Large-Cell, Anaplastic
  • NF-kappa B
  • Receptor Protein-Tyrosine Kinases
  • TNF Receptor-Associated Factor 1
  • Translocation, Genetic

abstract

  • Although anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human patient-derived tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and nuclear factor kB (NFkB) pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells, lacking PRDM1/Blimp1 and carrying c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to the downregulation of p50/p52 and lymphoma growth inhibition. Moreover, a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Although a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, nevertheless the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable tools to validate the role of druggable molecules, predict therapeutic responses and implement patient specific therapies.

authors

publication date

  • January 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4864432

Digital Object Identifier (DOI)

  • 10.1038/leu.2014.347

PubMed ID

  • 25533804

Additional Document Info

start page

  • 1390

end page

  • 401

volume

  • 29

number

  • 6