IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33739-2.html
   My bibliography  Save this article

Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape

Author

Listed:
  • Maurizio Mangolini

    (University of Cambridge
    University of Cambridge)

  • Alba Maiques-Diaz

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Stella Charalampopoulou

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS))

  • Elena Gerhard-Hartmann

    (Pathologisches Institut Universität Würzburg)

  • Johannes Bloehdorn

    (Ulm University)

  • Andrew Moore

    (University of Cambridge
    University of Cambridge)

  • Giorgia Giachetti

    (University of Cambridge
    University of Cambridge)

  • Junyan Lu

    (European Molecular Biology Laboratory (EMBL)
    Molecular Medicine Partnership Unit (MMPU))

  • Valar Nila Roamio Franklin

    (University of Cambridge)

  • Chandra Sekkar Reddy Chilamakuri

    (University of Cambridge)

  • Ilias Moutsopoulos

    (University of Cambridge)

  • Andreas Rosenwald

    (Pathologisches Institut Universität Würzburg)

  • Stephan Stilgenbauer

    (Ulm University)

  • Thorsten Zenz

    (University Hospital Zürich and University of Zürich
    National Center for Tumor Diseases and German Cancer, Research Centre)

  • Irina Mohorianu

    (University of Cambridge)

  • Clive D’Santos

    (University of Cambridge)

  • Silvia Deaglio

    (University of Turin)

  • Daniel J. Hodson

    (University of Cambridge
    University of Cambridge)

  • Jose I. Martin-Subero

    (Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Ingo Ringshausen

    (University of Cambridge
    University of Cambridge)

Abstract

Hotspot mutations in the PEST-domain of NOTCH1 and NOTCH2 are recurrently identified in B cell malignancies. To address how NOTCH-mutations contribute to a dismal prognosis, we have generated isogenic primary human tumor cells from patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), differing only in their expression of the intracellular domain (ICD) of NOTCH1 or NOTCH2. Our data demonstrate that both NOTCH-paralogs facilitate immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-γ signaling. In addition, NOTCH-activation causes silencing of the entire HLA-class II locus via epigenetic regulation of the transcriptional co-activator CIITA. Notably, while NOTCH1 and NOTCH2 govern similar transcriptional programs, disease-specific differences in their expression levels can favor paralog-specific selection. Importantly, NOTCH-ICD also strongly down-regulates the expression of CD19, possibly limiting the effectiveness of immune-therapies. These NOTCH-mediated immune escape mechanisms are associated with the expansion of exhausted CD8+ T cells in vivo.

Suggested Citation

  • Maurizio Mangolini & Alba Maiques-Diaz & Stella Charalampopoulou & Elena Gerhard-Hartmann & Johannes Bloehdorn & Andrew Moore & Giorgia Giachetti & Junyan Lu & Valar Nila Roamio Franklin & Chandra Sek, 2022. "Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33739-2
    DOI: 10.1038/s41467-022-33739-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33739-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33739-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jason Ernst & Pouya Kheradpour & Tarjei S. Mikkelsen & Noam Shoresh & Lucas D. Ward & Charles B. Epstein & Xiaolan Zhang & Li Wang & Robbyn Issner & Michael Coyne & Manching Ku & Timothy Durham & Mano, 2011. "Mapping and analysis of chromatin state dynamics in nine human cell types," Nature, Nature, vol. 473(7345), pages 43-49, May.
    2. Xose S. Puente & Silvia Beà & Rafael Valdés-Mas & Neus Villamor & Jesús Gutiérrez-Abril & José I. Martín-Subero & Marta Munar & Carlota Rubio-Pérez & Pedro Jares & Marta Aymerich & Tycho Baumann & Ren, 2015. "Non-coding recurrent mutations in chronic lymphocytic leukaemia," Nature, Nature, vol. 526(7574), pages 519-524, October.
    3. Evangelia K. Papachristou & Kamal Kishore & Andrew N. Holding & Kate Harvey & Theodoros I. Roumeliotis & Chandra Sekhar Reddy Chilamakuri & Soleilmane Omarjee & Kee Ming Chia & Alex Swarbrick & Elgene, 2018. "A quantitative mass spectrometry-based approach to monitor the dynamics of endogenous chromatin-associated protein complexes," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    4. Dan A. Landau & Eugen Tausch & Amaro N. Taylor-Weiner & Chip Stewart & Johannes G. Reiter & Jasmin Bahlo & Sandra Kluth & Ivana Bozic & Mike Lawrence & Sebastian Böttcher & Scott L. Carter & Kristian , 2015. "Mutations driving CLL and their evolution in progression and relapse," Nature, Nature, vol. 526(7574), pages 525-530, October.
    5. Maurizio Mangolini & Frederik Götte & Andrew Moore & Tim Ammon & Madlen Oelsner & Gloria Lutzny-Geier & Ludger Klein-Hitpass & James C. Williamson & Paul J. Lehner & Jan Dürig & Michael Möllmann & Lív, 2018. "Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sophie A. Herbst & Mattias Vesterlund & Alexander J. Helmboldt & Rozbeh Jafari & Ioannis Siavelis & Matthias Stahl & Eva C. Schitter & Nora Liebers & Berit J. Brinkmann & Felix Czernilofsky & Tobias R, 2022. "Proteogenomics refines the molecular classification of chronic lymphocytic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Seungsoo Hahn & Dongsup Kim, 2015. "Identifying and Reducing Systematic Errors in Chromosome Conformation Capture Data," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-17, December.
    3. Ye Cai & Huifen Cao & Fang Wang & Yufei Zhang & Philipp Kapranov, 2022. "Complex genomic patterns of abasic sites in mammalian DNA revealed by a high-resolution SSiNGLe-AP method," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    4. Chirag Nepal & Jesper B. Andersen, 2023. "Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Haoxi Chai & Harianto Tjong & Peng Li & Wei Liao & Ping Wang & Chee Hong Wong & Chew Yee Ngan & Warren J. Leonard & Chia-Lin Wei & Yijun Ruan, 2023. "ChIATAC is an efficient strategy for multi-omics mapping of 3D epigenomes from low-cell inputs," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Jacob Gordon & Fleur L. Chapus & Elizabeth G. Viverette & Jason G. Williams & Leesa J. Deterding & Juno M. Krahn & Mario J. Borgnia & Joseph Rodriguez & Alan J. Warren & Robin E. Stanley, 2022. "Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Zhangyuan Pan & Yuelin Yao & Hongwei Yin & Zexi Cai & Ying Wang & Lijing Bai & Colin Kern & Michelle Halstead & Ganrea Chanthavixay & Nares Trakooljul & Klaus Wimmers & Goutam Sahana & Guosheng Su & M, 2021. "Pig genome functional annotation enhances the biological interpretation of complex traits and human disease," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    8. Gerard Llimos & Vincent Gardeux & Ute Koch & Judith F. Kribelbauer & Antonina Hafner & Daniel Alpern & Joern Pezoldt & Maria Litovchenko & Julie Russeil & Riccardo Dainese & Riccardo Moia & Abdurraouf, 2022. "A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    9. Carlos Rivera & Hun-Goo Lee & Anna Lappala & Danni Wang & Verónica Noches & Montserrat Olivares-Costa & Marcela Sjöberg-Herrera & Jeannie T. Lee & María Estela Andrés, 2022. "Unveiling RCOR1 as a rheostat at transcriptionally permissive chromatin," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Kakushadze, Zura & Yu, Willie, 2016. "Factor models for cancer signatures," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 462(C), pages 527-559.
    11. Noah Dukler & Mehreen R. Mughal & Ritika Ramani & Yi-Fei Huang & Adam Siepel, 2022. "Extreme purifying selection against point mutations in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    12. Ting Shen & Ting Ni & Jiaxuan Chen & Haitao Chen & Xiaopin Ma & Guangwen Cao & Tianzhi Wu & Haisheng Xie & Bin Zhou & Gang Wei & Hexige Saiyin & Suqin Shen & Peng Yu & Qianyi Xiao & Hui Liu & Yuzheng , 2022. "An enhancer variant at 16q22.1 predisposes to hepatocellular carcinoma via regulating PRMT7 expression," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    13. Julia Truch & Damien J. Downes & Caroline Scott & E. Ravza Gür & Jelena M. Telenius & Emmanouela Repapi & Ron Schwessinger & Matthew Gosden & Jill M. Brown & Stephen Taylor & Pak Leng Cheong & Jim R. , 2022. "The chromatin remodeller ATRX facilitates diverse nuclear processes, in a stochastic manner, in both heterochromatin and euchromatin," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    14. Roberta Esposito & Andrés Lanzós & Tina Uroda & Sunandini Ramnarayanan & Isabel Büchi & Taisia Polidori & Hugo Guillen-Ramirez & Ante Mihaljevic & Bernard Mefi Merlin & Lia Mela & Eugenio Zoni & Lusin, 2023. "Tumour mutations in long noncoding RNAs enhance cell fitness," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    15. Jieqiong Zhang & Zhenhua Hu & Hwa Hwa Chung & Yun Tian & Kah Weng Lau & Zheng Ser & Yan Ting Lim & Radoslaw M. Sobota & Hwei Fen Leong & Benjamin Jieming Chen & Clarisse Jingyi Yeo & Shawn Ying Xuan T, 2023. "Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    16. Rachel K. Lex & Weiqiang Zhou & Zhicheng Ji & Kristin N. Falkenstein & Kaleigh E. Schuler & Kathryn E. Windsor & Joseph D. Kim & Hongkai Ji & Steven A. Vokes, 2022. "GLI transcriptional repression is inert prior to Hedgehog pathway activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    17. Othman Al-Sawaf & Can Zhang & Hyun Yong Jin & Sandra Robrecht & Yoonha Choi & Sandhya Balasubramanian & Alex Kotak & Yi Meng Chang & Anna Maria Fink & Eugen Tausch & Christof Schneider & Matthias Ritg, 2023. "Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    18. Zhaoyun Ding & Ting Cai & Jupei Tang & Hanxiao Sun & Xinyi Qi & Yunpeng Zhang & Yan Ji & Liyun Yuan & Huidan Chang & Yanhui Ma & Hong Zhou & Li Li & Huiming Sheng & Ju Qiu, 2022. "Setd2 supports GATA3+ST2+ thymic-derived Treg cells and suppresses intestinal inflammation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    19. Jennifer P. Nguyen & Timothy D. Arthur & Kyohei Fujita & Bianca M. Salgado & Margaret K. R. Donovan & Hiroko Matsui & Ji Hyun Kim & Agnieszka D’Antonio-Chronowska & Matteo D’Antonio & Kelly A. Frazer, 2023. "eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    20. Janek S. Walker & Zachary A. Hing & Steven Sher & James Cronin & Katie Williams & Bonnie Harrington & Jordan N. Skinner & Casey B. Cempre & Charles T. Gregory & Alexander Pan & Max Yano & Larry P. Bea, 2021. "Rare t(X;14)(q28;q32) translocation reveals link between MTCP1 and chronic lymphocytic leukemia," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33739-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.