PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas

1] Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria. [2].
Nature medicine (Impact Factor: 27.36). 10/2012; 18(11). DOI: 10.1038/nm.2966
Source: PubMed


Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.

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    • "The work presented here demonstrates that lobatin B is an active principle isolated from the DCM fraction of the methanolic extract of N. lobata and suppresses the NPM/ALK transcript and protein and also nucleophosmin, which, in its truncated form, is the 5-prime fusion partner of the NPM/ALK t(2;5)(p23;q35) translocation [3]. This suggested that a transcriptional mechanism responsible for nucleophosmin expression was hampered by lobatin B. NPM/ALK was shown to induce JunB, which is a transcription factor of the tyrosine receptor kinase PDGF-Rβ [10] [28] and lobatin B inhibited the expression of JunB and PDGF-Rβ subsequently to NPM/ALK down-regulation. Interestingly, the inactive sesquiterpene lactone OH-CAL downregulated JunB independently of NPM/ ALK and hence, also the effect of lobatin B on JunB might be more complex than just inhibiting gene expression downstream of NPM/ ALK signaling. "
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    ABSTRACT: An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this early step of metastatic progression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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    • "To further corroborate our results, we analyzed the expression levels of JUNB protein in experimentally induced mouse nucleophosmin-anaplastic-lymphoma-kinase (NPM-ALK) driven T-cell lymphomas [15] being wildtype, hemizygous or negative for JunB. JunB deletion was achieved in T-cells facilitating a CD4 driven CRE and a floxed JunB construct [17]. The genotypes of the T-cell lymphomas isolated from 10–18 week old mice were JunB wildtype (NPM-ALK/JunB+/+), JunB hemizygous (NPM-ALK/JunB+/Δ) and lacked JunB completely (NPM-ALK/JunBΔ/Δ). "
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    • "Among genes with tumor-specific retentions, genes with known driver functions in cancer were rediscovered, including EGFR, ROS1, ATM and KDR. Additionally, other growth factor genes were also found with retained introns in tumor samples, such as PDGFRB (platelet-derived growth factor receptor, beta polypeptide), TGFBI (transforming growth factor, beta-induced), EGF (epidermal growth factor), IGF2R (insulin-like growth factor 2 receptor), and ERBB2 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2), which are also involved in tumor evolution in various studies [58-62]. By detailed investigation, we found intron retentions within these genes all caused frame-shift changes, which tend to invoke NMD. "
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