title: Loss of T cell progenitor checkpoint control underlies leukemia initiation in Rag1-deficient nonobese diabetic mice.
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.
authors: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. yui@caltech.edu
authors: Mary A
authors: MA
authors: Yui
authors: Ni
authors: N
authors: Feng
authors: Jingli A
authors: JA
authors: Zhang
authors: Chen Yee
authors: CY
authors: Liaw
authors: Ellen V
authors: EV
authors: Rothenberg
authors: Jeffrey A
authors: JA
authors: Longmate
mesh_terms: D000199:Actins / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology / Q000378:metabolism*; D040641:Quantitative Trait Loci; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000199:Actins; D018398:Homeodomain Proteins; C064658:RAG-1 protein