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Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

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Title:Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability
Creators Name:Barbosa, R.R. and Xu, A.Q. and D'Andrea, D. and Copley, F. and Patel, H. and Chakravarty, P. and Clear, A. and Calaminici, M. and Janz, M. and Zhang, B. and Schmidt-Supprian, M. and Wang, J. and Gribben, J.G. and Tooze, R. and Fitzgibbon, J. and Franzoso, G. and Rajewsky, K. and Calado, D.P.
Abstract:NF-κB and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-κB is necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus unclear if NF-κB/MYC co-deregulation is developmentally compatible in carcinogenesis and/or impacts cancer cell differentiation state, possibly uncovering unique sensitivities. Using a mouse system to trace cell lineage and oncogene activation we found that NF-κB/MYC co-deregulation originated cancers with a plasmablast-like phenotype, alike human plasmablastic-lymphoma and was linked to t(8;14)[MYC-IGH] multiple myeloma. Notably, in contrast to NF-κB or MYC activation alone, co-deregulation rendered cells addicted to IL6 for survival and phenotypic stability. We propose that conflicting oncogene-driven differentiation pressures can be accommodated at a cost in poorly-differentiated cancers. SIGNIFICANCE: Our studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of NF-κB and MYC synergize in forming a cancer with a poorly-differentiated state. The cancers in the mouse system share features with human Plasmablastic lymphoma that has a dismal prognosis and no standard of care, and with t(8;14)[MYC-IGH] Multiple myeloma, which is in overall resistant to standard therapy. Notably, we found that NF-κB and MYC co-deregulation uniquely render cells sensitive to IL6 deprivation, providing a road-map for patient selection. Because of the similarity of the cancers arising in the compound mutant mouse model with that of human Plasmablastic lymphoma and t(8;14)[MYC-IGH] Multiple myeloma, this model could serve in preclinical testing to investigate novel therapies for these hard-to-treat diseases.
Keywords:NF-kB, MYC, IL6, B-Cell, Plasma-Cell, Plasmablast, B-Cell Terminal Differentiation, Diffuse Large B-Cell Lymphoma, Plasmablastic Lymphoma, Multiple Myeloma, Phenotypic Stability, Animals, Mice
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.04.12.038414
Date:13 April 2020
Official Publication:https://doi.org/10.1101/2020.04.12.038414

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