title: TCR-dependent transformation of mature memory phenotype T cells in mice.
abstract: A fundamental goal in cancer research is the identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth, as this has the potential to reveal therapeutic targets. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies. However, the identity of the cells in which mature lymphoid neoplasms are initiated remains unclear. Here, we investigate the origin of peripheral T cell lymphomas using mice in which Snf5, a chromatin remodelling-complex subunit with tumor suppressor activity, could be conditionally inactivated in developing T cells. In this model of mature peripheral T cell lymphomas, the cell of origin was a mature CD44hiCD122loCD8⁺ T cell that resembled a subset of memory cells that has capacity for self-renewal and robust expansion, features shared with stem cells. Further analysis showed that Snf5 loss led to activation of a Myc-driven signaling network and stem cell transcriptional program. Finally, lymphomagenesis and lymphoma proliferation depended upon TCR signaling, establishing what we believe to be a new paradigm for lymphoid malignancy growth. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells are associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Miriam B F
authors.initials: MB
authors.lastname: Werneck
authors.forename: Boris G
authors.initials: BG
authors.lastname: Wilson
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Thom
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Wischhusen
authors.forename: Julia A
authors.initials: JA
authors.lastname: Evans
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Jesneck
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Sansam
authors.forename: Harvey
authors.initials: H
authors.lastname: Cantor
authors.forename: Charles W M
authors.initials: CW
authors.lastname: Roberts
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000276:immunology*; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D007156:Immunologic Memory; D016411:Lymphoma, T-Cell, Peripheral / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D000071796:SMARCB1 Protein; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell; D000071796:SMARCB1 Protein; C513265:Smarcb1 protein, mouse