title: Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors.
abstract: Inhibitor of DNA binding (Id) proteins, including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins is associated with a broad spectrum of tumors, recent studies have identified that Id3 plays a tumor-suppressor role in the development of Burkitt's lymphoma in humans and hepatosplenic T cell lymphomas in mice. In this article, we report rapid lymphoma development inId2/Id3double-knockout mice that is caused by unchecked expansion of invariant NKT (iNKT) cells or a unique subset of innate-like CD1d-independent T cells. These populations began to expand in neonatal mice and, upon malignant transformation, resulted in mortality between 3 and 11 mo of age. The malignant cells also gave rise to lymphomas upon transfer toRag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. Microarray analysis revealed a significantly modified program in these neonatal iNKT cells that ultimately led to their malignant transformation. The lymphoma cells demonstrated chromosome instability along with upregulation of several signaling pathways, including the cytokine-cytokine receptor interaction pathway, which can promote their expansion and migration. Dysregulation of genes with reported driver mutations and the NF-κB pathway were found to be shared betweenId2/Id3double-knockout lymphomas and human NKT tumors. Our work identifies a distinct premalignant state and multiple tumorigenic pathways caused by loss of function of Id2 and Id3. Thus, conditional deletion ofId2andId3in developing T cells establishes a unique animal model for iNKT and relevant innate-like lymphomas.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Jia
authors.identifier: 0000-0003-3070-8635
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Sumedha
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Pediatrics, Oklahoma University Health Sciences Center, Oklahoma City, OK 73014.
authors.forename: Young-Mi
authors.identifier: 0000-0002-2766-0071
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Oklahoma University Health Sciences Center, Oklahoma City, OK 73014.
authors.forename: Shibo
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710.
authors.forename: Baojun
authors.identifier: 0000-0002-7786-4304
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710; and.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Love
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710; and.
authors.forename: Anupama
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710; and.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Rajagopalan
authors.affiliation: Duke Institute for Genome Sciences and Policy, Duke University, Durham, NC 27710; and.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dave
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710; yzhuang@duke.edu.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhuang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000276:immunology*; D051796:Inhibitor of Differentiation Proteins / Q000276:immunology*; D008223:Lymphoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; C067679:Idb3 protein, mouse