A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation

F. Abate, M. Todaro, J. A. Van Der Krogt, M. Boi, I. Landra, R. Machiorlatti, F. Tabbò, K. Messana, C. Abele, A. Barreca, D. Novero, M. Gaudiano, S. Aliberti, F. Di Giacomo, T. Tousseyn, E. Lasorsa, R. Crescenzo, L. Bessone, E. Ficarra, A. AcquavivaA. Rinaldi, M. Ponzoni, D. L. Longo, S. Aime, M. Cheng, B. Ruggeri, P. P. Piccaluga, S. Pileri, E. Tiacci, B. Falini, B. Pera-Gresely, L. Cerchietti, J. Iqbal, W. C. Chan, L. D. Shultz, I. Kwee, R. Piva, I. Wlodarska, R. Rabadan, F. Bertoni, G. Inghirami

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1390-1401
Number of pages12
JournalLeukemia
Volume29
Issue number6
DOIs
Publication statusPublished - Jun 9 2015

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine
  • Medicine(all)

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    Abate, F., Todaro, M., Van Der Krogt, J. A., Boi, M., Landra, I., Machiorlatti, R., Tabbò, F., Messana, K., Abele, C., Barreca, A., Novero, D., Gaudiano, M., Aliberti, S., Di Giacomo, F., Tousseyn, T., Lasorsa, E., Crescenzo, R., Bessone, L., Ficarra, E., ... Inghirami, G. (2015). A novel patient-derived tumorgraft model with TRAF1-ALK anaplastic large-cell lymphoma translocation. Leukemia, 29(6), 1390-1401. https://doi.org/10.1038/leu.2014.347