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Loss of T Cell Progenitor Checkpoint Control Underlies Leukemia Initiation in Rag1-Deficient Nonobese Diabetic Mice

Yui, Mary A. and Feng, Ni and Zhang, Jingli A. and Liaw, Chen Yee and Rothenberg, Ellen V. and Longmate, Jeffrey A. (2013) Loss of T Cell Progenitor Checkpoint Control Underlies Leukemia Initiation in Rag1-Deficient Nonobese Diabetic Mice. Journal of Immunology, 190 (7). pp. 3276-3288. ISSN 0022-1767. PMCID PMC3608698. https://resolver.caltech.edu/CaltechAUTHORS:20130506-110729222

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Abstract

NOD mice exhibit major defects in the earliest stages of T cell development in the thymus. Genome-wide genetic and transcriptome analyses were used to investigate the origins and consequences of an early T cell developmental checkpoint breakthrough in Rag1-deficient NOD mice. Quantitative trait locus analysis mapped the presence of checkpoint breakthrough cells to several known NOD diabetes susceptibility regions, particularly insulin-dependent diabetes susceptibility genes (Idd)9/11 on chromosome 4, suggesting common genetic origins for T cell defects affecting this trait and autoimmunity. Genome-wide RNA deep-sequencing of NOD and B6 Rag1-deficient thymocytes revealed the effects of genetic background prior to breakthrough, as well as the cellular consequences of the breakthrough. Transcriptome comparison between the two strains showed enrichment in differentially expressed signal transduction genes, prominently tyrosine kinase and actin-binding genes, in accord with their divergent sensitivities to activating signals. Emerging NOD breakthrough cells aberrantly expressed both stem cell–associated proto-oncogenes, such as Lmo2, Hhex, Lyl1, and Kit, which are normally repressed at the commitment checkpoint, and post–β-selection checkpoint genes, including Cd2 and Cd5. Coexpression of genes characteristic of multipotent progenitors and more mature T cells persists in the expanding population of thymocytes and in the thymic leukemias that emerge with age in these mice. These results show that Rag1-deficient NOD thymocytes have T cell defects that can collapse regulatory boundaries at two early T cell checkpoints, which may predispose them to both leukemia and autoimmunity.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.4049/jimmunol.1202970DOIArticle
http://jimmunol.org/content/190/7/3276PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608698/PubMed CentralArticle
ORCID:
AuthorORCID
Yui, Mary A.0000-0002-3136-2181
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2013 by The American Association of Immunologists, Inc. Received October 31, 2012. Accepted January 21, 2013. Published online before print February 25, 2013. This work was supported by National Institutes of Health Grant AI64590 (to M.A.Y.); California Institute of Technology Summer Undergraduate Research Fellowships (to C.Y.L.); the Albert Billings Ruddock Professorship (to E.V.R.); the Louis A. Garfinkle Memorial Laboratory Fund; and the Al Sherman Foundation. We thank Brian Williams, Justine Chia, Avni Gandhi, and Sagar Damle (California Institute of Technology) for technical and bioinformatics assistance; Donna Walls and Weidong Zhang (The Jackson Laboratory) for genotyping and preliminary statistical analysis; J.C. Zuñiga-Pflücker (University of Toronto) for providing OP9-DL1 and OP9-DL4 cells; L.S. Wicker (Cambridge University) for NOD.B10Idd9 congenic mice; Rochelle Diamond, Diane Perez, and Pat Koen from the California Institute of Technology Flow Cytometry and Cell Sorting Facility; Scott Washburn and Natasha Bouey for animal care; and Ali Mortazavi and members of the Rothenberg Laboratory for helpful suggestions. The authors have no financial conflicts of interest.
Funders:
Funding AgencyGrant Number
NIHAI64590
Caltech Summer Undergraduate Research Fellowship (SURF)UNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
Al Sherman FoundationUNSPECIFIED
Issue or Number:7
PubMed Central ID:PMC3608698
Record Number:CaltechAUTHORS:20130506-110729222
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130506-110729222
Official Citation:Loss of T Cell Progenitor Checkpoint Control Underlies Leukemia Initiation in Rag1-Deficient Nonobese Diabetic Mice Mary A. Yui, Ni Feng, Jingli A. Zhang, Chen Yee Liaw, Ellen V. Rothenberg, and Jeffrey A. Longmate J Immunol 2013 190:3276-3288; published ahead of print February 25, 2013, doi:10.4049/jimmunol.1202970
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:38294
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:06 May 2013 20:21
Last Modified:03 Oct 2019 04:55

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