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

Huan-Chang Liang; Mariantonia Costanza; Nicole Prutsch; Mark W Zimmerman; Elisabeth Gurnhofer; Ivonne A Montes-Mojarro; Brian J Abraham; Nina Prokoph; Stefan Stoiber; Simone Tangermann; Cosimo Lobello; Jan Oppelt; Ioannis Anagnostopoulos; Thomas Hielscher; Shahid Pervez; Wolfram Klapper; Francesca Zammarchi; Daniel-Adriano Silva; K Christopher Garcia; David Baker; Martin Janz; Nikolai Schleussner; Falko Fend; Šárka Pospíšilová; Andrea Janiková; Jacqueline Wallwitz; Dagmar Stoiber; Ingrid Simonitsch-Klupp; Lorenzo Cerroni; Stefano Pileri; Laurence de Leval; David Sibon; Virginie Fataccioli; Philippe Gaulard; Chalid Assaf; Fabian Knörr; Christine Damm-Welk; Wilhelm Woessmann; Suzanne D Turner; A Thomas Look; Stephan Mathas; Lukas Kenner; Olaf Merkel

doi:10.1038/s41467-021-25379-9

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

Huan-Chang Liang, Mariantonia Costanza, Nicole Prutsch, Mark W Zimmerman, Elisabeth Gurnhofer, Ivonne A Montes-Mojarro, Brian J Abraham, Nina Prokoph, Stefan Stoiber, Simone Tangermann, Cosimo Lobello, Jan Oppelt, Ioannis Anagnostopoulos, Thomas Hielscher, Shahid Pervez, Wolfram Klapper, Francesca Zammarchi, Daniel-Adriano Silva, K Christopher Garcia, David BakerMartin Janz, Nikolai Schleussner, Falko Fend, Šárka Pospíšilová, Andrea Janiková, Jacqueline Wallwitz, Dagmar Stoiber, Ingrid Simonitsch-Klupp, Lorenzo Cerroni, Stefano Pileri, Laurence de Leval, David Sibon, Virginie Fataccioli, Philippe Gaulard, Chalid Assaf, Fabian Knörr, Christine Damm-Welk, Wilhelm Woessmann, Suzanne D Turner, A Thomas Look, Stephan Mathas, Lukas Kenner, Olaf Merkel

Division of Pharmacology

Research output: Journal article (peer-reviewed) › Journal article

22 Citations (Scopus)

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.

Original language	English
Article number	5577
Pages (from-to)	5577
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25379-9
Publication status	Published - 01 Dec 2021

Keywords

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

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10.1038/s41467-021-25379-9

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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., ... Merkel, O. (2021). Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma. Nature Communications, 12(1), 5577. Article 5577. https://doi.org/10.1038/s41467-021-25379-9

@article{5aafdcb5a096412494e0bcd6328aa4f9,

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

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 = "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",

author = "Huan-Chang Liang and Mariantonia Costanza and Nicole Prutsch and Zimmerman, {Mark W} and Elisabeth Gurnhofer and Montes-Mojarro, {Ivonne A} and Abraham, {Brian J} and Nina Prokoph and Stefan Stoiber and Simone Tangermann and Cosimo Lobello and Jan Oppelt and Ioannis Anagnostopoulos and Thomas Hielscher and Shahid Pervez and Wolfram Klapper and Francesca Zammarchi and Daniel-Adriano Silva and Garcia, {K Christopher} and David Baker and Martin Janz and Nikolai Schleussner and Falko Fend and {\v S}{\'a}rka Posp{\'i}{\v s}ilov{\'a} and Andrea Janikov{\'a} and Jacqueline Wallwitz and Dagmar Stoiber and Ingrid Simonitsch-Klupp and Lorenzo Cerroni and Stefano Pileri and {de Leval}, Laurence and David Sibon and Virginie Fataccioli and Philippe Gaulard and Chalid Assaf and Fabian Kn{\"o}rr and Christine Damm-Welk and Wilhelm Woessmann and Turner, {Suzanne D} and Look, {A Thomas} and Stephan Mathas and Lukas Kenner and Olaf Merkel",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-25379-9",

language = "English",

volume = "12",

pages = "5577",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Liang, H-C, Costanza, M, Prutsch, N, Zimmerman, MW, Gurnhofer, E, Montes-Mojarro, IA, Abraham, BJ, Prokoph, N, Stoiber, S, Tangermann, S, Lobello, C, Oppelt, J, Anagnostopoulos, I, Hielscher, T, Pervez, S, Klapper, W, Zammarchi, F, Silva, D-A, Garcia, KC, 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, SD, Look, AT, Mathas, S, Kenner, L & Merkel, O 2021, 'Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma', Nature Communications, vol. 12, no. 1, 5577, pp. 5577. https://doi.org/10.1038/s41467-021-25379-9

TY - JOUR

T1 - Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma

AU - Liang, Huan-Chang

AU - Costanza, Mariantonia

AU - Prutsch, Nicole

AU - Zimmerman, Mark W

AU - Gurnhofer, Elisabeth

AU - Montes-Mojarro, Ivonne A

AU - Abraham, Brian J

AU - Prokoph, Nina

AU - Stoiber, Stefan

AU - Tangermann, Simone

AU - Lobello, Cosimo

AU - Oppelt, Jan

AU - Anagnostopoulos, Ioannis

AU - Hielscher, Thomas

AU - Pervez, Shahid

AU - Klapper, Wolfram

AU - Zammarchi, Francesca

AU - Silva, Daniel-Adriano

AU - Garcia, K Christopher

AU - Baker, David

AU - Janz, Martin

AU - Schleussner, Nikolai

AU - Fend, Falko

AU - Pospíšilová, Šárka

AU - Janiková, Andrea

AU - Wallwitz, Jacqueline

AU - Stoiber, Dagmar

AU - Simonitsch-Klupp, Ingrid

AU - Cerroni, Lorenzo

AU - Pileri, Stefano

AU - de Leval, Laurence

AU - Sibon, David

AU - Fataccioli, Virginie

AU - Gaulard, Philippe

AU - Assaf, Chalid

AU - Knörr, Fabian

AU - Damm-Welk, Christine

AU - Woessmann, Wilhelm

AU - Turner, Suzanne D

AU - Look, A Thomas

AU - Mathas, Stephan

AU - Kenner, Lukas

AU - Merkel, Olaf

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Basic-Leucine Zipper Transcription Factors/genetics

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - Cell Survival/drug effects

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunoconjugates/pharmacology

KW - Interleukin-15/pharmacology

KW - Interleukin-2/pharmacology

KW - Interleukin-2 Receptor alpha Subunit/genetics

KW - Ki-1 Antigen/genetics

KW - Lymphoma, Large-Cell, Anaplastic/drug therapy

KW - Mice

KW - Receptors, Interleukin-2/genetics

KW - Regulatory Sequences, Nucleic Acid

KW - Repressor Proteins/genetics

KW - Signal Transduction/drug effects

KW - Xenograft Model Antitumor Assays

UR - http://www.scopus.com/inward/record.url?scp=85115414234&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-25379-9

DO - 10.1038/s41467-021-25379-9

M3 - Journal article

C2 - 34552066

SN - 2041-1723

VL - 12

SP - 5577

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5577

ER -

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

Abstract

Keywords

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