title: Transmembrane TNF-α preferentially expressed by leukemia stem cells and blasts is a potent target for antibody therapy.
abstract: To design an effective antibody therapy to improve clinical outcomes in leukemia, the identification of novel cell surface antigens is needed. Herein, we demonstrate a role for transmembrane tumor necrosis factor-α (tmTNF-α) in leukemia. To characterize tmTNF-α expression in acute leukemia (AL), normal hematopoietic cells, and nonhematopoietic tissues, we used a monoclonal antibody, termed C1, which specifically recognizes the tmTNF-α domain. We found that tmTNF-α was preferentially expressed by AL and leukemia stem cells (LSCs). More abundant expression correlated with poor risk stratification, extramedullary infiltration, and adverse clinical parameters. Moreover, knockdown of tmTNF-α(+) expression rendered leukemia cells more sensitive to chemotherapy in vitro and delayed regeneration of leukemia in NOD-SCID mice. Targeting tmTNF-α by C1 resulted in leukemia cell killing via antibody-dependent cell-mediated and complement-dependent cytotoxicity in vitro and inhibited leukemia cell growth in vivo while simultaneously sparing normal hematopoietic cells. Notably, C1 administration impaired the regeneration of leukemia in secondary serial transplantation into NOD-SCID mice. In conclusion, tmTNF-α has a favorable AL- and LSC-associated expression profile and is important for the survival and proliferation of these cells. C1-mediated targeting shows potent anti-LSC activity, indicating that tmTNF-α represents a novel target antigen in AL.
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Shiqiu
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Immunology, Basic Medical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Baihua
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Qinlu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Lili
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Quan
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Basic Medical College, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhuoya
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Hematology, Tongji Hospital, Wuhan, China; and.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000276:immunology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007167:Immunotherapy; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins