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.

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; A., Barreca; D., Novero; M., Gaudiano; S., Aliberti; F., Di Giacomo; T., Tousseyn; E., Lasorsa; R., Crescenzo; L., Bessone; Ficarra, Elisa; Acquaviva, Andrea; A., Rinaldi; M., Ponzoni; Dl, Longo; S., Aime; M., Cheng; B., Ruggeri; Pp, Piccaluga; S., Pileri; E., Tiacci; B., Falini; B., Pera Gresely; L., Cerchietti; J., Iqbal; Wc, Chan; Ld, Shultz; I., Kwee; R., Piva; I., Wlodarska; R., Rabadan; F., Bertoni; G., Inghirami; The European T., cell Lymphoma Study Group. - In: LEUKEMIA. - ISSN 0887-6924. - 29:6(2015), pp. 1390-1401. [10.1038/leu.2014.347]

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

FICARRA, ELISA;
2015-01-01

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.
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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; A., Barreca; D., Novero; M., Gaudiano; S., Aliberti; F., Di Giacomo; T., Tousseyn; E., Lasorsa; R., Crescenzo; L., Bessone; Ficarra, Elisa; Acquaviva, Andrea; A., Rinaldi; M., Ponzoni; Dl, Longo; S., Aime; M., Cheng; B., Ruggeri; Pp, Piccaluga; S., Pileri; E., Tiacci; B., Falini; B., Pera Gresely; L., Cerchietti; J., Iqbal; Wc, Chan; Ld, Shultz; I., Kwee; R., Piva; I., Wlodarska; R., Rabadan; F., Bertoni; G., Inghirami; The European T., cell Lymphoma Study Group. - In: LEUKEMIA. - ISSN 0887-6924. - 29:6(2015), pp. 1390-1401. [10.1038/leu.2014.347]
F., Abate; M., Todaro; J. A., van der Krogt; M., Boi; I., Landra; R., Machiorlatti; F., Tabbò; K., Messana; A., Barreca; D., Novero; M., Gaudiano; S., Aliberti; F., Di Giacomo; T., Tousseyn; E., Lasorsa; R., Crescenzo; L., Bessone; Ficarra, Elisa; Acquaviva, Andrea; A., Rinaldi; M., Ponzoni; Dl, Longo; S., Aime; M., Cheng; B., Ruggeri; Pp, Piccaluga; S., Pileri; E., Tiacci; B., Falini; B., Pera Gresely; L., Cerchietti; J., Iqbal; Wc, Chan; Ld, Shultz; I., Kwee; R., Piva; I., Wlodarska; R., Rabadan; F., Bertoni; G., Inghirami; The European T., cell Lymphoma Study Group
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1240383
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