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

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 of NFkB pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells lacking PRDM1/Blimp-1 and with c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to down-regulation of p50/p52 and lymphoma growth inhibition. Moreover a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Moreover, a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, but 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 to validate the role of druggable molecules, predict therapeutic responses and are helpful tools for the implementation of patient specific therapies.

Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma

“…A total of 28 fusions were identified and validated (Figures 5A and S5), including four NPM-ALK and one TRAF1-ALK (Abate et al, 2014a) chimeras in the five ALK + cases. Four of 18 ALK − ALCLs displayed fusion transcripts involving tyrosine kinases (TKs) known to play a pathogenetic role either in hematologic or solid neoplasms (Shaw et al, 2013) (Figure 5B), with two ALCLs bearing more than one fusion (Table S7) all in the absence of JAK1 or STAT3 mutations.…”

Crizotinib induces apoptosis and gene expression changes in ALK+ anaplastic large cell lymphoma cell lines; brentuximab synergizes and doxorubicin antagonizes

“…Affected regulators of apoptosis include BCL3 , a member of the IkB family that modulates the activation of NF‐kB . Differential expression of NF‐kB associated transcripts NFKB1, RELA , and RELB is further consistent with the role of NF‐kB deregulation in ALCL . This may have future therapeutic implications in terms of Nf‐kB inhibitors such as bortezomib.…”

“…53 Differential expression of NF-kB associated transcripts NFKB1, RELA, and RELB is further consistent with the role of NF-kB deregulation in ALCL. 54 This may have future therapeutic implications in terms of Nf-kB inhibitors F I G U R E 3 Volcano plots show fold change of gene expression versus significance, -log10 (P-value), with drug treatments of cell lines. (A) Genes differentially expressed with crizotinib; those above the dotted line showed adjusted P < 0.05.…”

Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type

“…Several examples of PDTX from human T-cell tumours have been reported, including acute T cell leukaemias (Guimaraes-Correa et al ., 2011; Agnusdei et al ., 2014) and one example of an anaplastic large T-cell lymphoma (Abate et al ., 2015). A cell line (OSW) derived from the pleural effusion of a dog with malignant peripheral T-cell lymphoma that forms tumour xenografts in SCID/NOD mice was reported (Kisseberth et al ., 2007).…”