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

Autor: Liang, Huan-Chang, Costanza, Mariantonia, Prutsch, Nicole, Zimmerman, Mark W., Gurnhofer, Elisabeth, Montes-Mojarro, Ivonne A., Abraham, Brian J., Prokoph, Nina, Stoiber, Stefan, Tangermann, Simone, Lobello, Cosimo, Oppelt, Jan, Anagnostopoulos, Ioannis, Hielscher, Thomas, Pervez, Shahid, Klapper, Wolfram, Zammarchi, Francesca, Silva, Daniel-Adriano, Garcia, K. Christopher, Baker, David, Janz, Martin, Schleussner, Nikolai, Fend, Falko, Pospíšilová, Šárka, Janiková, Andrea, Wallwitz, Jacqueline, Stoiber, Dagmar, Simonitsch-Klupp, Ingrid, Cerroni, Lorenzo, Pileri, Stefano, de Leval, Laurence, Sibon, David, Fataccioli, Virginie, Gaulard, Philippe, Assaf, Chalid, Knörr, Fabian, Damm-Welk, Christine, Woessmann, Wilhelm, Turner, Suzanne D., Look, A. Thomas, Mathas, Stephan, Kenner, Lukas, Merkel, Olaf
Přispěvatelé: Liang, Huan-Chang [0000-0003-2612-3714], Costanza, Mariantonia [0000-0002-8959-1083], Zimmerman, Mark W. [0000-0003-2489-3889], Montes-Mojarro, Ivonne A. [0000-0003-0636-7623], Abraham, Brian J. [0000-0001-8085-3027], Prokoph, Nina [0000-0002-6429-9895], Stoiber, Stefan [0000-0003-3293-867X], Oppelt, Jan [0000-0002-3076-4840], Klapper, Wolfram [0000-0001-7208-4117], Silva, Daniel-Adriano [0000-0002-3195-9009], Garcia, K. Christopher [0000-0001-9273-0278], Baker, David [0000-0001-7896-6217], Janz, Martin [0000-0002-1127-0044], Fend, Falko [0000-0002-5496-293X], de Leval, Laurence [0000-0003-3994-516X], Turner, Suzanne D. [0000-0002-8439-4507], Look, A. Thomas [0000-0001-7851-8617], Mathas, Stephan [0000-0001-9626-1413], Kenner, Lukas [0000-0003-2184-1338], Merkel, Olaf [0000-0001-5089-344X], Apollo - University of Cambridge Repository, Zimmerman, Mark W [0000-0003-2489-3889], Montes-Mojarro, Ivonne A [0000-0003-0636-7623], Abraham, Brian J [0000-0001-8085-3027], Garcia, K Christopher [0000-0001-9273-0278], Turner, Suzanne D [0000-0002-8439-4507], Look, A Thomas [0000-0001-7851-8617]
Rok vydání: 2021
Předmět:
CRISPR-Cas9 genome editing
Cancer Research
Immunoconjugates
Cell Survival
Science
Ki-1 Antigen
Regulatory Sequences
Nucleic Acid
631/67/1990/291/1621/1916
38/91
96/95
Mice
Cell Line
Tumor
hemic and lymphatic diseases
Animals
Humans
Cell Proliferation
Interleukin-15
High-throughput screening
Interleukin-2 Receptor alpha Subunit
article
Receptors
Interleukin-2
Basic-Leucine Zipper Transcription Factors/genetics
Basic-Leucine Zipper Transcription Factors/metabolism
Cell Proliferation/drug effects
Cell Survival/drug effects
Gene Expression Regulation
Neoplastic
Immunoconjugates/pharmacology
Interleukin-15/pharmacology
Interleukin-2/pharmacology
Interleukin-2 Receptor alpha Subunit/genetics
Interleukin-2 Receptor alpha Subunit/immunology
Interleukin-2 Receptor alpha Subunit/metabolism
Ki-1 Antigen/genetics
Ki-1 Antigen/metabolism
Lymphoma
Large-Cell
Anaplastic/drug therapy
Lymphoma
Large-Cell
Anaplastic/genetics
Lymphoma
Large-Cell
Anaplastic/metabolism
Lymphoma
Large-Cell
Anaplastic/pathology
Receptors
Interleukin-2/genetics
Receptors
Interleukin-2/immunology
Receptors
Interleukin-2/metabolism
Repressor Proteins/genetics
Repressor Proteins/metabolism
Signal Transduction/drug effects
Xenograft Model Antitumor Assays
45/15
96/21
Repressor Proteins
631/337/4041/3196
Mechanisms of disease
Basic-Leucine Zipper Transcription Factors
Interleukin-2
Lymphoma
Large-Cell
Anaplastic
T-cell lymphoma
631/1647/2163
631/80/304
82/51
Signal Transduction
Zdroj: Nature communications, vol. 12, no. 1, pp. 5577
Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021)
Popis: 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.
Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL.
Databáze: OpenAIRE
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