title: NKp46 identifies an NKT cell subset  susceptible to leukemic transformation  in mouse and human.
abstract: IL-15 may have a role in the development of T cell large granular lymphocyte (T-LGL) or NKT leukemias. However, the mechanisms of action and the identity of the cell subset that undergoes leukemic transformation remain elusive. Here we show that in both mice and humans, NKp46 expression marks a minute population of WT NKT cells with higher activity and potency to become leukemic. Virtually 100% of T-LGL leukemias in IL-15 transgenic mice expressed NKp46, as did a majority of human T-LGL leukemias. The minute NKp46+ NKT population, but not the NKp46⁻ NKT population, was selectively expanded by overexpression of endogenous IL-15. Importantly, IL-15 transgenic NKp46⁻ NKT cells did not become NKp46+ in vivo, suggesting that NKp46+ T-LGL leukemia cells were the malignant counterpart of the minute WT NKp46+ NKT population. Mechanistically, NKp46+ NKT cells possessed higher responsiveness to IL-15 in vitro and in vivo compared with that of their NKp46⁻ NKT counterparts. Furthermore, interruption of IL-15 signaling using a neutralizing antibody could prevent LGL leukemia in IL-15 transgenic mice. Collectively, our data demonstrate that NKp46 identifies a functionally distinct NKT subset in mice and humans that appears to be directly susceptible to leukemic transformation when IL-15 is overexpressed. Thus, IL-15 signaling and NKp46 may be useful targets in the treatment of patients with T-LGL or NKT leukemia.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA. Jianhua.yu@osumc.edu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Takeki
authors.initials: T
authors.lastname: Mitsui
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Butchar
authors.forename: Mithun Vinod
authors.initials: MV
authors.lastname: Shah
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Christopher
authors.initials: C
authors.lastname: Alvarez-Breckenridge
authors.forename: Xingluo
authors.initials: X
authors.lastname: Liu
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yokohama
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000037:antagonists & inhibitors; D054066:Leukemia, Large Granular Lymphocytic / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000145:classification / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000145:classification / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; C508022:Il2rb protein, mouse; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse