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IRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma

Author

Listed:
  • Stella Amanda

    (National University of Singapore)

  • Tze King Tan

    (National University of Singapore)

  • Jolynn Zu Lin Ong

    (National University of Singapore)

  • Madelaine Skolastika Theardy

    (National University of Singapore)

  • Regina Wan Ju Wong

    (National University of Singapore)

  • Xiao Zi Huang

    (National University of Singapore)

  • Muhammad Zulfaqar Ali

    (National University of Singapore)

  • Yan Li

    (National University of Singapore)

  • Zhiyuan Gong

    (National University of Singapore)

  • Hiroshi Inagaki

    (Nagoya City University Graduate School of Medical Sciences)

  • Ee Yong Foo

    (National University of Singapore)

  • Brendan Pang

    (National University of Singapore)

  • Soo Yong Tan

    (National University of Singapore)

  • Shinsuke Iida

    (Nagoya City University Graduate School of Medical Sciences)

  • Takaomi Sanda

    (National University of Singapore
    National University of Singapore)

Abstract

IRF4 is a master regulator of immunity and is also frequently overexpressed in mature lymphoid neoplasms. Here, we demonstrate the oncogenicity of IRF4 in vivo, its potential effects on T-cell development and clonal evolution using a zebrafish model. IRF4-transgenic zebrafish develop aggressive tumors with massive infiltration of abnormal lymphocytes that spread to distal organs. Many late-stage tumors are mono- or oligoclonal, and tumor cells can expand in recipient animals after transplantation, demonstrating their malignancy. Mutation of p53 accelerates tumor onset, increases penetrance, and results in tumor heterogeneity. Surprisingly, single-cell RNA-sequencing reveals that the majority of tumor cells are double-negative T-cells, many of which express tcr-γ that became dominant as the tumors progress, whereas double-positive T-cells are largely diminished. Gene expression and epigenetic profiling demonstrates that gata3, mycb, lrrn1, patl1 and psip1 are specifically activated in tumors, while genes responsible for T-cell differentiation including id3 are repressed. IRF4-driven tumors are sensitive to the BRD inhibitor.

Suggested Citation

  • Stella Amanda & Tze King Tan & Jolynn Zu Lin Ong & Madelaine Skolastika Theardy & Regina Wan Ju Wong & Xiao Zi Huang & Muhammad Zulfaqar Ali & Yan Li & Zhiyuan Gong & Hiroshi Inagaki & Ee Yong Foo & B, 2022. "IRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30053-9
    DOI: 10.1038/s41467-022-30053-9
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