title: Thymic expression of a T-cell receptor targeting a tumor-associated antigen coexpressed in the thymus induces T-ALL.
abstract: T-cell receptors (TCRs) and chimeric antigen receptors recognizing tumor-associated antigens (TAAs) can now be engineered to be expressed on a wide array of immune effectors. Engineered receptors targeting TAAs have most commonly been expressed on mature T cells, however, some have postulated that receptor expression on immune progenitors could yield T cells with enhanced potency. We generated mice (survivin-TCR-transgenic [Sur-TCR-Tg]) expressing a TCR recognizing the immunodominant epitope (Sur20-28) of murine survivin during early stages of thymopoiesis. Spontaneous T-cell acute lymphoblastic leukemia (T-ALL) occurred in 100% of Sur-TCR-Tg mice derived from 3 separate founders. The leukemias expressed the Sur-TCR and signaled in response to the Sur20-28 peptide. In preleukemic mice, we observed increased cycling of double-negative thymocytes expressing the Sur-TCR and increased nuclear translocation of nuclear factor of activated T cells, consistent with TCR signaling induced by survivin expression in the murine thymus. β2M(-/-) Sur-TCR-Tg mice, which cannot effectively present survivin peptides on class I major histocompatibility complex, had significantly diminished rates of leukemia. We conclude that TCR signaling during the early stages of thymopoiesis mediates an oncogenic signal, and therefore expression of signaling receptors on developing thymocytes with specificity for TAAs expressed in the thymus could pose a risk for neoplasia, independent of insertional mutagenesis.
authors: Pediatric Oncology Branch and.
authors: Yongzhi
authors: Y
authors: Cui
authors: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;
authors: Masahiro
authors: M
authors: Onozawa
authors: Pediatric Oncology Branch and.
authors: Haven R
authors: HR
authors: Garber
authors: Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors: Leigh
authors: L
authors: Samsel
authors: Pediatric Oncology Branch and.
authors: Ziyao
authors: Z
authors: Wang
authors: Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors: J Philip
authors: JP
authors: McCoy
authors: Molecular Cytogenetics Core, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD; and.
authors: Sandra
authors: S
authors: Burkett
authors: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD.
authors: Xiaolin
authors: X
authors: Wu
authors: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD;
authors: Peter D
authors: PD
authors: Aplan
authors: Pediatric Oncology Branch and.
authors: Crystal L
authors: CL
authors: Mackall
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000502:physiology; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077022:Survivin; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; C117749:Birc5 protein, mouse; D015815:Cell Adhesion Molecules; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; D000077022:Survivin; C476587:Taa1 protein, mouse; C064658:RAG-1 protein