PUBLICATION
IRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma
- Authors
- Amanda, S., Tan, T.K., Ong, J.Z.L., Theardy, M.S., Wong, R.W.J., Huang, X.Z., Ali, M.Z., Li, Y., Gong, Z., Inagaki, H., Foo, E.Y., Pang, B., Tan, S.Y., Iida, S., Sanda, T.
- ID
- ZDB-PUB-220506-15
- Date
- 2022
- Source
- Nature communications 13: 2420 (Journal)
- Registered Authors
- Gong, Zhiyuan, Sanda, Takaomi
- Keywords
- none
- Datasets
- GEO:GSE166650, GEO:GSE166644, GEO:GSE184946, GEO:GSE139226, GEO:GSE166646
- MeSH Terms
-
- Animals
- Cell Differentiation
- Clonal Evolution
- Lymphoma*/genetics
- Lymphoma, T-Cell*
- Zebrafish/genetics
- PubMed
- 35504924 Full text @ Nat. Commun.
Citation
Amanda, S., Tan, T.K., Ong, J.Z.L., Theardy, M.S., Wong, R.W.J., Huang, X.Z., Ali, M.Z., Li, Y., Gong, Z., Inagaki, H., Foo, E.Y., Pang, B., Tan, S.Y., Iida, S., Sanda, T. (2022) IRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma. Nature communications. 13:2420.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping