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

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, Brendan Pang, Soo Yong Tan, Shinsuke Iida and Takaomi Sanda ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30053-9

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