Genetic landscape of T cells identifies synthetic lethality for T-ALL

O’Meara, Connor P.; Guerri, Lucia; Lawir, Divine-Fondzenyuy; Mateos, Fernando; Iconomou, Mary; Iwanami, Norimasa; Soza-Ried, Cristian; Sikora, Katarzyna; Siamishi, Iliana; Giorgetti, Orlando Bruno; Peter, Sarah; Schorpp, Michael; Boehm, Thomas

doi:10.1038/s42003-021-02694-x

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Genetic landscape of T cells identifies synthetic lethality for T-ALL

MPS-Authors

O’Meara, Connor P.
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Guerri, Lucia
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lawir, Divine-Fondzenyuy
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Mateos, Fernando
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Iconomou, Mary
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Iwanami, Norimasa
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Soza-Ried, Cristian
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sikora, Katarzyna
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Siamishi, Iliana
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Giorgetti, Orlando Bruno
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Peter, Sarah
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Schorpp, Michael
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Boehm, Thomas
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.nature.com/articles/s42003-021-02694-x
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O Meara et al. 2021.pdf
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Citation

O’Meara, C. P., Guerri, L., Lawir, D.-F., Mateos, F., Iconomou, M., Iwanami, N., et al. (2021). Genetic landscape of T cells identifies synthetic lethality for T-ALL. Communications Biology, 4: 1201. doi:10.1038/s42003-021-02694-x.

Cite as: https://hdl.handle.net/21.11116/0000-0009-95F6-9

Abstract

To capture the global gene network regulating the differentiation of immature T cells in an unbiased manner, large-scale forward genetic screens in zebrafish were conducted and combined with genetic interaction analysis. After ENU mutagenesis, genetic lesions associated with failure of T cell development were identified by meiotic recombination mapping, positional cloning, and whole genome sequencing. Recessive genetic variants in 33 genes were identified and confirmed as causative by additional experiments. The mutations affected T cell development but did not perturb the development of an unrelated cell type, growth hormone-expressing somatotrophs, providing an important measure of cell-type specificity of the genetic variants. The structure of the genetic network encompassing the identified components was established by a subsequent genetic interaction analysis, which identified many instances of positive (alleviating) and negative (synthetic) genetic interactions. Several examples of synthetic lethality were subsequently phenocopied using combinations of small molecule inhibitors. These drugs not only interfered with normal T cell development, but also elicited remission in a model of T cell acute lymphoblastic leukaemia. Our findings illustrate how genetic interaction data obtained in the context of entire organisms can be exploited for targeted interference with specific cell types and their malignant derivatives.