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

J 2021

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

LIANG, H.C., M. COSTANZA, N. PRUTSCH, M.W. ZIMMERMAN, E. GURNHOFER et. al.

Basic information

Original name

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

Authors

LIANG, H.C., M. COSTANZA, N. PRUTSCH, M.W. ZIMMERMAN, E. GURNHOFER, I.A. MONTES-MOJARRO, B.J. ABRAHAM, N. PROKOPH, S. STOIBER, S. TANGERMANN, Cosimo LOBELLO (380 Italy, belonging to the institution), Jan OPPELT (203 Czech Republic, belonging to the institution), I. ANAGNOSTOPOULOS, T. HIELSCHER, S. PERVEZ, W. KLAPPER, F. ZAMMARCHI, D.A. SILVA, K.C. GARCIA, D. BAKER, M. JANZ, N. SCHLEUSSNER, F. FEND, Šárka POSPÍŠILOVÁ (203 Czech Republic, guarantor, belonging to the institution), A. JANIKOVA, J. WALLWITZ, D. STOIBER, I. SIMONITSCH-KLUPP, L. CERRONI, S. PILERI, L. DE LEVAL, D. SIBON, V. FATACCIOLI, P. GAULARD, C. ASSAF, F. KNORR, C. DAMM-WELK, W. WOESSMANN, Suzanne Dawn TURNER (826 United Kingdom of Great Britain and Northern Ireland, belonging to the institution), A.T. LOOK, S. MATHAS, L. KENNER and O. MERKEL

Edition

Nature Communications, London, Nature Publishing Group, 2021, 2041-1723

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

Germany

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 17.694

RIV identification code

RIV/00216224:14740/21:00123350

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1038/s41467-021-25379-9

UT WoS

000700360600032

Keywords in English

HODGKIN LYMPHOMANPM-ALKCD30 PROMOTERKINASEANTIBODYTUMORTRANSLOCATIONSINHIBITIONDIAGNOSISIDENTITY

Abstract

V originále

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-2R alpha-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2R alpha-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-2R alpha-targeting as a promising treatment strategy for ALCL.

Links

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

675712, interní kód MU

Name: ALK Activation as a target of TRAanslational Science (ALKATRAS): Break free from cancer (Acronym: ALKATRAS)

Investor: European Union, MSCA Marie Skłodowska-Curie Actions (Excellent Science)

90132, large research infrastructures

Name: NCMG II

Citovat

LIANG, H.C., M. COSTANZA, N. PRUTSCH, M.W. ZIMMERMAN, E. GURNHOFER, I.A. MONTES-MOJARRO, B.J. ABRAHAM, N. PROKOPH, S. STOIBER, S. TANGERMANN, Cosimo LOBELLO, Jan OPPELT, I. ANAGNOSTOPOULOS, T. HIELSCHER, S. PERVEZ, W. KLAPPER, F. ZAMMARCHI, D.A. SILVA, K.C. GARCIA, D. BAKER, M. JANZ, N. SCHLEUSSNER, F. FEND, Šárka POSPÍŠILOVÁ, A. JANIKOVA, J. WALLWITZ, D. STOIBER, I. SIMONITSCH-KLUPP, L. CERRONI, S. PILERI, L. DE LEVAL, D. SIBON, V. FATACCIOLI, P. GAULARD, C. ASSAF, F. KNORR, C. DAMM-WELK, W. WOESSMANN, Suzanne Dawn TURNER, A.T. LOOK, S. MATHAS, L. KENNER and O. MERKEL. Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma. Nature Communications. London: Nature Publishing Group, 2021, vol. 12, No 1, p. 5577-5588. ISSN 2041-1723. Available from: https://dx.doi.org/10.1038/s41467-021-25379-9.

@article{1812960,
   author = {Liang, H.C. and Costanza, M. and Prutsch, N. and Zimmerman, M.W. and Gurnhofer, E. and MontesandMojarro, I.A. and Abraham, B.J. and Prokoph, N. and Stoiber, S. and Tangermann, S. and Lobello, Cosimo and Oppelt, Jan 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, Šárka and Janikova, A. and Wallwitz, J. and Stoiber, D. and SimonitschandKlupp, I. and Cerroni, L. and Pileri, S. and de Leval, L. and Sibon, D. and Fataccioli, V. and Gaulard, P. and Assaf, C. and Knorr, F. and DammandWelk, C. and Woessmann, W. and Turner, Suzanne Dawn and Look, A.T. and Mathas, S. and Kenner, L. and Merkel, O.},
   article_location = {London},
   article_number = {1},
   doi = {http://dx.doi.org/10.1038/s41467-021-25379-9},
   keywords = {HODGKIN LYMPHOMANPM-ALKCD30 PROMOTERKINASEANTIBODYTUMORTRANSLOCATIONSINHIBITIONDIAGNOSISIDENTITY},
   language = {eng},
   issn = {2041-1723},
   journal = {Nature Communications},
   title = {Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma},
   url = {https://www.nature.com/articles/s41467-021-25379-9},
   volume = {12},
   year = {2021}
}

TY  - JOUR
ID  - 1812960
AU  - 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, Cosimo - Oppelt, Jan - 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, Šárka - Janikova, A. - Wallwitz, J. - Stoiber, D. - Simonitsch-Klupp, I. - Cerroni, L. - Pileri, S. - de Leval, L. - Sibon, D. - Fataccioli, V. - Gaulard, P. - Assaf, C. - Knorr, F. - Damm-Welk, C. - Woessmann, W. - Turner, Suzanne Dawn - Look, A.T. - Mathas, S. - Kenner, L. - Merkel, O.
PY  - 2021
TI  - Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma
JF  - Nature Communications
VL  - 12
IS  - 1
SP  - 5577
EP  - 5577
PB  - Nature Publishing Group
SN  - 20411723
KW  - HODGKIN LYMPHOMANPM-ALKCD30 PROMOTERKINASEANTIBODYTUMORTRANSLOCATIONSINHIBITIONDIAGNOSISIDENTITY
UR  - https://www.nature.com/articles/s41467-021-25379-9
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-2R alpha-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2R alpha-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-2R alpha-targeting as a promising treatment strategy for ALCL.
ER  -

LIANG, H.C., M. COSTANZA, N. PRUTSCH, M.W. ZIMMERMAN, E. GURNHOFER, I.A. MONTES-MOJARRO, B.J. ABRAHAM, N. PROKOPH, S. STOIBER, S. TANGERMANN, Cosimo LOBELLO, Jan OPPELT, I. ANAGNOSTOPOULOS, T. HIELSCHER, S. PERVEZ, W. KLAPPER, F. ZAMMARCHI, D.A. SILVA, K.C. GARCIA, D. BAKER, M. JANZ, N. SCHLEUSSNER, F. FEND, Šárka POSPÍŠILOVÁ, A. JANIKOVA, J. WALLWITZ, D. STOIBER, I. SIMONITSCH-KLUPP, L. CERRONI, S. PILERI, L. DE LEVAL, D. SIBON, V. FATACCIOLI, P. GAULARD, C. ASSAF, F. KNORR, C. DAMM-WELK, W. WOESSMANN, Suzanne Dawn TURNER, A.T. LOOK, S. MATHAS, L. KENNER and O. MERKEL. Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma. \textit{Nature Communications}. London: Nature Publishing Group, 2021, vol.~12, No~1, p.~5577-5588. ISSN~2041-1723. Available from: https://dx.doi.org/10.1038/s41467-021-25379-9.

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