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| Item Type: | Article |
|---|---|
| Title: | Autocrine LTA signaling drives NF-κB and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma |
| Creators: |
von Hoff, L., Kärgel, E., Franke, V.  ORCID: https://orcid.org/0000-0003-3606-6792, McShane, E. ORCID: https://orcid.org/0000-0002-7806-2063, Schulz-Beiss, K.W., Patone, G. ORCID: https://orcid.org/0000-0002-7242-0341, Schleussner, N. ORCID: https://orcid.org/0009-0001-3549-5600, Kolesnichenko, M. ORCID: https://orcid.org/0000-0001-7366-9061, Hübner, N. ORCID: https://orcid.org/0000-0002-1218-6223, Daumke, O. ORCID: https://orcid.org/0000-0002-6190-1414, Selbach, M. ORCID: https://orcid.org/0000-0003-2454-8751, Akalin, A. ORCID: https://orcid.org/0000-0002-0468-0117, Mathas, S. ORCID: https://orcid.org/0000-0001-9626-1413 and Scheidereit, C. ORCID: https://orcid.org/0000-0002-0446-6129
|
| Abstract: | Persistent NF-κB activation is a hallmark of the malignant Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL). Genomic lesions, Epstein-Barr virus infection, soluble factors and tumor-microenvironment interactions contribute to this activation. Here, in an unbiased approach to identify the cHL cell-secreted key factors for NF-κB activation, we have dissected the secretome of cultured cHL cells by chromatography and subsequent mass spectrometry. We identified lymphotoxin-α (LTA) as the causative factor for autocrine and paracrine activation of canonical and non-canonical NF-κB in cHL cell lines. Apart from inducing NF-κB, LTA promotes JAK2/STAT6 signaling. LTA and its receptor TNFRSF14 are transcriptionally activated by non-canonical NF-κB, creating a continuous feedback loop. Furthermore, LTA shapes the expression of cytokines, receptors, immune checkpoint ligands and adhesion molecules, including CSF2, CD40, PD-L1/-L2 and VCAM1. Comparison with single cell gene-activity profiles of human hematopoietic cells showed that LTA not only induces genes restricted to the lymphoid but also largely to the myeloid lineage. Thus, LTA sustains autocrine NF-κB activation, impacts activation of several signaling pathways and drives expression of genes essential for microenvironmental interactions and lineage ambiguity. These data provide a robust rationale for LTA-targeting as a treatment strategy for cHL patients. |
| Keywords: | Cell Line, Hodgkin Disease, Janus Kinase 2, Lymphotoxin-alpha, NF-kappa B, Neoplastic Gene Expression Regulation, Reed-Sternberg Cells, STAT6 Transcription Factor, Signal Transduction, Transcriptional Activation |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 133 |
| Number: | 13 |
| Page Range: | 1489-1494 |
| Date: | 28 March 2019 |
| Additional Information: | Copyright © 2019 by The American Society of Hematology |
| Official Publication: | https://doi.org/10.1182/blood-2018-08-871293 |
| PubMed: | View item in PubMed |
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