Aberrant activation of NF-κB is the most striking oncogenic mechanism in B-cell lymphoma; however, its role in anaplastic large cell lymphomas (ALCL) has not been fully established and its activation mechanism(s) remain unclear. Using ALCL cell line models, we revealed the supporting roles for NFKB2 and the NIK pathway in some ALCL lines. To investigate the detailed activation mechanisms for this oncogenic pathway, we performed specifically designed alternative NF-κB reporter CRISPR screens followed by the RNA-seq analysis, which led us to identify STAT3 as the major mediator for NIK-dependent NF-κB activation in ALCL. Consistently, p-STAT3 level was correlated with NFKB2 nuclear accumulation in primary clinical samples. Mechanistically, we found that in NIK-positive ALK− ALCL cells, common JAK/STAT3 mutations promote transcriptional activity of STAT3 which directly regulates NFKB2 and CD30 expression. Endogenous expression of CD30 induces constitutive NF-κB activation through binding and degrading of TRAF3. In ALK+ ALCL, the CD30 pathway is blocked by the NPM–ALK oncoprotein, but STAT3 activity and resultant NFKB2 expression can still be induced by NPM–ALK, leading to minimal alternative NF-κB activation. Our data suggest combined NIK and JAK inhibitor therapy could benefit patients with NIK-positive ALK− ALCL carrying JAK/STAT3 somatic mutations.
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This research was supported by American Cancer Society (ASC) IRG-92-027-21 (YY), and the Medical Research Grant from the WW. SMITH Charitable Trust (YY). The study was supported in part by the Intramural Research Program of the National Cancer Institute, NIH. The authors thank the patients for their participation. We thank D. L. Wiest (FCCC) and K.S. Campbell (FCCC) for discussions and comments. We also thank Dr. Alan L. Epstein (USC Keck School of Medicine) for the TLBR1 and TLBR2 cell lines and Dr. Annarosa Del Mistro (The Veneto Institute of Oncology) for the FE-PD cell line.
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Wang, H., Wei, W., Zhang, JP. et al. A novel model of alternative NF-κB pathway activation in anaplastic large cell lymphoma. Leukemia (2020). https://doi.org/10.1038/s41375-020-01088-y