1. Transmembrane TNF-α preferentially expressed by leukemia stem cells and blasts is a potent target for antibody therapy.
- Author
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Zhou X, Zhou S, Li B, Li Q, Gao L, Li D, Gong Q, Zhu L, Wang J, Wang N, Huang L, Zhao L, Li Z, and Zhou J
- Subjects
- Animals, Antibodies, Monoclonal immunology, Cell Line, Tumor, Complement System Proteins immunology, Gene Expression Regulation, Leukemic, Humans, Immunotherapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute pathology, Mice, Inbred NOD, Mice, SCID, Neoplastic Stem Cells immunology, Neoplastic Stem Cells metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Tumor Necrosis Factor-alpha analysis, Tumor Necrosis Factor-alpha genetics, Antibodies, Monoclonal therapeutic use, Leukemia, Myeloid, Acute therapy, Neoplastic Stem Cells pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Tumor Necrosis Factor-alpha immunology
- 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., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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