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

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 ce...

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Main Authors: Connor P. O’Meara, Lucia Guerri, Divine-Fondzenyuy Lawir, Fernando Mateos, Mary Iconomou, Norimasa Iwanami, Cristian Soza-Ried, Katarzyna Sikora, Iliana Siamishi, Orlando Giorgetti, Sarah Peter, Michael Schorpp, Thomas Boehm
Format: Article
Language:English
Published: Nature Portfolio 2021-10-01
Series:Communications Biology
Online Access:https://doi.org/10.1038/s42003-021-02694-x
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author Connor P. O’Meara
Lucia Guerri
Divine-Fondzenyuy Lawir
Fernando Mateos
Mary Iconomou
Norimasa Iwanami
Cristian Soza-Ried
Katarzyna Sikora
Iliana Siamishi
Orlando Giorgetti
Sarah Peter
Michael Schorpp
Thomas Boehm
author_facet Connor P. O’Meara
Lucia Guerri
Divine-Fondzenyuy Lawir
Fernando Mateos
Mary Iconomou
Norimasa Iwanami
Cristian Soza-Ried
Katarzyna Sikora
Iliana Siamishi
Orlando Giorgetti
Sarah Peter
Michael Schorpp
Thomas Boehm
author_sort Connor P. O’Meara
collection DOAJ
description 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.
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spelling doaj.art-336c81ef888e42abb79749a16438e1dd2024-03-05T20:00:09ZengNature PortfolioCommunications Biology2399-36422021-10-014111810.1038/s42003-021-02694-xGenetic landscape of T cells identifies synthetic lethality for T-ALLConnor P. O’Meara0Lucia Guerri1Divine-Fondzenyuy Lawir2Fernando Mateos3Mary Iconomou4Norimasa Iwanami5Cristian Soza-Ried6Katarzyna Sikora7Iliana Siamishi8Orlando Giorgetti9Sarah Peter10Michael Schorpp11Thomas Boehm12Department of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsBioinformatics Unit, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsBioinformatics Unit, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and EpigeneticsAbstract 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.https://doi.org/10.1038/s42003-021-02694-x
spellingShingle Connor P. O’Meara
Lucia Guerri
Divine-Fondzenyuy Lawir
Fernando Mateos
Mary Iconomou
Norimasa Iwanami
Cristian Soza-Ried
Katarzyna Sikora
Iliana Siamishi
Orlando Giorgetti
Sarah Peter
Michael Schorpp
Thomas Boehm
Genetic landscape of T cells identifies synthetic lethality for T-ALL
Communications Biology
title Genetic landscape of T cells identifies synthetic lethality for T-ALL
title_full Genetic landscape of T cells identifies synthetic lethality for T-ALL
title_fullStr Genetic landscape of T cells identifies synthetic lethality for T-ALL
title_full_unstemmed Genetic landscape of T cells identifies synthetic lethality for T-ALL
title_short Genetic landscape of T cells identifies synthetic lethality for T-ALL
title_sort genetic landscape of t cells identifies synthetic lethality for t all
url https://doi.org/10.1038/s42003-021-02694-x
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