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| Item Type: | Article |
|---|---|
| Title: | Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma |
| Creators Name: | Liang, H.C., Costanza, M., Prutsch, N., Zimmerman, M.W., Gurnhofer, E., Montes-Mojarro, I.A., Abraham, B.J., Prokoph, N., Stoiber, S., Tangermann, S., Lobello, C., Oppelt, J., Anagnostopoulos, I., Hielscher, T., Pervez, S., Klapper, W., Zammarchi, F., Silva, D.A., Garcia, K.C., Baker, D., Janz, M., Schleussner, N., Fend, F., Pospíšilová, Š., Janiková, A., Wallwitz, J., Stoiber, D., Simonitsch-Klupp, I., Cerroni, L., Pileri, S., de Leval, L., Sibon, D., Fataccioli, V., Gaulard, P., Assaf, C., Knörr, F., Damm-Welk, C., Woessmann, W., Turner, S.D., Look, A.T., Mathas, S., Kenner, L. and Merkel, O. |
| Abstract: | Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL. |
| Keywords: | Anaplastic Lymphoma, Large-Cell, Basic-Leucine Zipper Transcription Factors, Cell Proliferation, Cell Survival, Immunoconjugates, Interleukin-15, Interleukin-2, Interleukin-2 Receptor alpha Subunit, Interleukin-2 Receptors, Ki-1 Antigen, Neoplastic Gene Expression Regulation, Nucleic Acid Regulatory Sequences, Repressor Proteins, Signal Transduction, Tumor Cell Line, Xenograft Model Antitumor Assays, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 12 |
| Number: | 1 |
| Page Range: | 5577 |
| Date: | 22 September 2021 |
| Official Publication: | https://doi.org/10.1038/s41467-021-25379-9 |
| PubMed: | View item in PubMed |
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