Abstract LB018: Clonal evolution and lineage choice driven by IRF4 in zebrafish T-cell lymphoma model

Abstract

Abstract IRF4 is a master regulator of immunity and is also frequently overexpressed in mature lymphoid neoplasms. Here, we demonstrate the stage-specific 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 significantly accelerates tumor onset, increases penetrance, and results in tumor heterogeneity. Unexpectedly, single-cell RNA-sequencing reveals that 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 enhancer profiling demonstrates that gata3, mycb and several genes that were previously not implicated in cancers including lrrn1, patl1 and psip1 are specifically upregulated in tumors, while genes responsible for T-cell differentiation including cxcr4b, id3 and cd8a are repressed. IRF4-driven tumors are sensitive to treatment with the BRD inhibitor (JQ1). Citation Format: Stella Amanda, Tze King Tan, Jolynn Zu Lin Ong, Madelaine Skolastika Theardy, Regina Wan Ju Wong, Xiao Zi Huang, Muhammad Zulfaqar Ali, Li Yan, Zhiyuan Gong, Hiroshi Inagaki, Ee Yong Foo, Brendan Pang, Soo Yong Tan, Shinsuke Iida, Takaomi Sanda. Clonal evolution and lineage choice driven by IRF4 in zebrafish T-cell lymphoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB018.