Helmholtz Gemeinschaft


Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma

PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
[img] Other (Supplementary Material)

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. and Costanza, M. and Prutsch, N. and Zimmerman, M.W. and Gurnhofer, E. and Montes-Mojarro, I.A. and Abraham, B.J. and Prokoph, N. and Stoiber, S. and Tangermann, S. and Lobello, C. and Oppelt, J. and Anagnostopoulos, I. and Hielscher, T. and Pervez, S. and Klapper, W. and Zammarchi, F. and Silva, D.A. and Garcia, K.C. and Baker, D. and Janz, M. and Schleussner, N. and Fend, F. and Pospíšilová, Š. and Janiková, A. and Wallwitz, J. and Stoiber, D. and Simonitsch-Klupp, I. and Cerroni, L. and Pileri, S. and de Leval, L. and Sibon, D. and Fataccioli, V. and Gaulard, P. and Assaf, C. and Knörr, F. and Damm-Welk, C. and Woessmann, W. and Turner, S.D. and Look, A.T. and Mathas, S. and 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
Publisher:Nature Publishing Group
Page Range:5577
Date:22 September 2021
Official Publication:https://doi.org/10.1038/s41467-021-25379-9
PubMed:View item in PubMed

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library