Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.
Animals
Basic-Leucine Zipper Transcription Factors
/ genetics
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Gene Expression Regulation, Neoplastic
Humans
Immunoconjugates
/ pharmacology
Interleukin-15
/ pharmacology
Interleukin-2
/ pharmacology
Interleukin-2 Receptor alpha Subunit
/ genetics
Ki-1 Antigen
/ genetics
Lymphoma, Large-Cell, Anaplastic
/ drug therapy
Mice
Receptors, Interleukin-2
/ genetics
Regulatory Sequences, Nucleic Acid
Repressor Proteins
/ genetics
Signal Transduction
/ drug effects
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 09 2021
22 09 2021
Historique:
received:
22
10
2020
accepted:
29
07
2021
entrez:
23
9
2021
pubmed:
24
9
2021
medline:
21
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34552066
doi: 10.1038/s41467-021-25379-9
pii: 10.1038/s41467-021-25379-9
pmc: PMC8458384
doi:
Substances chimiques
BATF3 protein, human
0
Basic-Leucine Zipper Transcription Factors
0
IL2RA protein, human
0
Immunoconjugates
0
Interleukin-15
0
Interleukin-2
0
Interleukin-2 Receptor alpha Subunit
0
Ki-1 Antigen
0
Receptors, Interleukin-2
0
Repressor Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5577Subventions
Organisme : NCI NIH HHS
ID : R35 CA210064
Pays : United States
Informations de copyright
© 2021. The Author(s).
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